Human ATPase proteins and polynucleotides encoding the same

ABSTRACT

Novel human polynucleotide and polypeptide sequences are disclosed that can be used in therapeutic, diagnostic, and pharmacogenomic applications.

The present application claims the benefit of U.S. ProvisionalApplication No. 60/164,624 which was filed on Nov. 10, 1999 and isherein incorporated by reference in its entirety.

1. INTRODUCTION

The present invention relates to the discovery, identification, andcharacterization of novel human polynucleotides encoding proteins thatshare sequence similarity with animal ATPase proteins. The inventionencompasses the described polynucleotides, host cell expression systems,the encoded proteins, fusion proteins, polypeptides and peptides,antibodies to the encoded proteins and peptides, and geneticallyengineered animals that either lack or over express the disclosed genes,antagonists and agonists of the proteins, and other compounds thatmodulate the expression or activity of the proteins encoded by thedisclosed genes that can be used for diagnosis, drug screening, clinicaltrial monitoring and the treatment of diseases and disorders.

2. BACKGROUND OF THE INVENTION

ATPases are proteins that mediate, facilitate, or “power” a wide varietyof chemical processes within the cell. For example, ATPases have beenassociated with enzymatic, catabolic, and metabolic processes as well astransport mechanisms, blood coagulation, phagocytosis, etc.

3. SUMMARY OF THE INVENTION

The present invention relates to the discovery, identification, andcharacterization of nucleotides that encode novel human proteins, andthe corresponding amino acid sequences of these proteins. The novelhuman proteins (NHPS) described for the first time herein sharestructural similarity with animal ATPases.

The novel human nucleic acid sequences described herein, encodealternative proteins/open reading frames (ORFs) of 972, 124, 1,056, 208,1,270, 422, 1,426, and 578 amino acids in length (see SEQ ID NOS: 2, 4,6, 8, 10, 12, 14, and 16 respectively).

The invention also encompasses agonists and antagonists of the describedNHPS, including small molecules, large molecules, mutant NHPs, orportions thereof that compete with native NHP, peptides, and antibodies,as well as nucleotide sequences that can be used to inhibit theexpression of the described NHPs (e.g., antisense and ribozymemolecules, and gene or regulatory sequence replacement constructs) or toenhance the expression of the described NHP genes (e.g., expressionconstructs that place the described gene under the control of a strongpromoter system), and transgenic animals that express a NHP transgene,or “knock-outs” (which can be conditional) that do not express afunctional NHP. A knockout ES cell line has been produced that containsa gene trap mutation in the murine ortholog of the described locus.

Further, the present invention also relates to processes for identifyingcompounds that modulate, i.e., act as agonists or antagonists, of NHPexpression and/or NHP activity that utilize purified preparations of thedescribed NHPs and/or NHP product, or cells expressing the same. Suchcompounds can be used as therapeutic agents for the treatment of any ofa wide variety of symptoms associated with biological disorders orimbalances.

4. DESCRIPTION OF THE SEQUENCE LISTING AND FIGURES

The Sequence Listing provides the sequences of the described NHP ORFsthat encode the described NHP amino acid sequences. SEQ ID NO:17describes a NHP ORF as well as flanking 5′ and 3′ sequences.

5. DETAILED DESCRIPTION OF THE INVENTION

The NHPS, described for the first time herein, are novel proteins thatare expressed in, inter alia, human cell lines, predominantly in humankidney and placenta, as well as human fetal brain, brain, pituitary,cerebellum, spinal cord, thymus, spleen, lymph node, bone marrow,trachea, fetal liver, prostate, testis, thyroid, adrenal gland, salivarygland, stomach, small intestine, colon, uterus, mammary gland, adipose,esophagus, bladder, cervix, rectum, ovary, fetal kidney, fetal lung andgene trapped human cells.

The present invention encompasses the nucleotides presented in theSequence Listing, host cells expressing such nucleotides, the expressionproducts of such nucleotides, and: (a) nucleotides that encode mammalianhomologs of the described genes, including the specifically describedNHPs, and the NHP products; (b) nucleotides that encode one or moreportions of the NHPs that correspond to functional domains, and thepolypeptide products specified by such nucleotide sequences, includingbut not limited to the novel regions of any active domain(s); (c)isolated nucleotides that encode mutant versions, engineered ornaturally occurring, of the described NHPs in which all or a part of atleast one domain is deleted or altered, and the polypeptide productsspecified by such nucleotide sequences, including but not limited tosoluble proteins and peptides in which all or a portion of the signalsequence in deleted; (d) nucleotides that encode chimeric fusionproteins containing all or a portion of a coding region of an NHP, orone of its domains (e.g., a receptor or ligand binding domain, accessoryprotein/self-association domain, etc.) fused to another peptide orpolypeptide; or (e) therapeutic or diagnostic derivatives of thedescribed polynucleotides such as oligonucleotides, antisensepolynucleotides, ribozymes, dsRNA, or gene therapy constructs comprisinga sequence first disclosed in the Sequence Listing.

As discussed above, the present invention includes: (a) the human DNAsequences presented in the Sequence Listing (and vectors comprising thesame) and additionally contemplates any nucleotide sequence encoding acontiguous NHP open reading frame (ORF) that hybridizes to a complementof a DNA sequence presented in the Sequence Listing under highlystringent conditions, e.g., hybridization to filter-bound DNA in 0.5 MNaHPO₄, 7% sodium dodecyl sulfate (SDS), 1 mM EDTA at 65° C., andwashing in 0.1×SSC/0.1% SDS at 68° C. (Ausubel F. M. et al., eds., 1989,Current Protocols in Molecular Biology, Vol. I, Green PublishingAssociates, Inc., and John Wiley & sons, Inc., New York, at p. 2.10.3)and encodes a functionally equivalent gene product. Additionallycontemplated are any nucleotide sequences that hybridize to thecomplement of a DNA sequence that encodes and expresses an amino acidsequence presented in the Sequence Listing under moderately stringentconditions, e.g., washing in 0.2×SSC/0.1% SDS at 42° C. (Ausubel et al.,1989, supra), yet still encodes a functionally equivalent NHP product.Functional equivalents of a NHP include naturally occurring NHPs presentin other species and mutant NHPs whether naturally occurring orengineered (by site directed mutagenesis, gene shuffling, directedevolution as described in, for example, U.S. Pat. No. 5,837,458). Theinvention also includes degenerate nucleic acid variants of thedisclosed NHP polynucleotide sequences.

Additionally contemplated are polynucleotides encoding NHP ORFs, ortheir functional equivalents, encoded by polynucleotide sequences thatare about 99, 95, 90, or about 85 percent similar or identical tocorresponding regions of the nucleotide sequences of the SequenceListing (as measured by BLAST sequence comparison analysis using, forexample, the GCG sequence analysis package using standard defaultsettings).

The invention also includes nucleic acid molecules, preferably DNAmolecules, that hybridize to, and are therefore the complements of, thedescribed NHP gene nucleotide sequences. Such hybridization conditionsmay be highly stringent or less highly stringent, as described above. Ininstances where the nucleic acid molecules are deoxyoligonucleotides(“DNA oligos”), such molecules are generally about 16 to about 100 baseslong, or about 20 to about 80, or about 34 to about 45 bases long, orany variation or combination of sizes represented therein thatincorporate a contiguous region of sequence first disclosed in theSequence Listing. Such oligonucleotides can be used in conjunction withthe polymerase chain reaction (PCR) to screen libraries, isolate clones,and prepare cloning and sequencing templates, etc.

Alternatively, such NHP oligonucleotides can be used as hybridizationprobes for screening libraries, and assessing gene expression patterns(particularly using a micro array or high-throughput “chip” format).Additionally, a series of the described NHP oligonucleotide sequences,or the complements thereof, can be used to represent all or a portion ofthe described NHP sequences. The oligonucleotides, typically betweenabout 16 to about 40 (or any whole number within the stated range)nucleotides in length can partially overlap each other and/or the NHPsequence may be represented using oligonucleotides that do not overlap.Accordingly, the described NHP polynucleotide sequences shall typicallycomprise at least about two or three distinct oligonucleotide sequencesof at least about 18, and preferably about 25, nucleotides in lengththat are each first disclosed in the described Sequence Listing. Sucholigonucleotide sequences may begin at any nucleotide present within asequence in the Sequence Listing and proceed in either a sense(5′-to-3′) orientation vis-a-vis the described sequence or in anantisense orientation.

For oligonucleotide probes, highly stringent conditions may refer, e.g.,to washing in 6×SSC/0.05% sodium pyrophosphate at 37° C. (for 14-baseoligos), 48° C. (for 17-base oligos), 55° C. (for 20-base oligos), and60° C. (for 23-base oligos). These nucleic acid molecules may encode oract as NHP gene antisense molecules, useful, for example, in NHP generegulation (for and/or as antisense primers in amplification reactionsof NHP gene nucleic acid sequences). With respect to NHP generegulation, such techniques can be used to regulate biologicalfunctions. Further, such sequences may be used as part of ribozymeand/or triple helix sequences that are also useful for NHP generegulation.

Inhibitory antisense or double stranded oligonucleotides canadditionally comprise at least one modified base moiety which isselected from the group including but not limited to 5-fluorouracil,5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine,4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil,5-carboxymethylaminomethyl-2-thiouridine,5-carboxymethylaminomethyluracil, dihydrouracil,beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine,7-methylguanine, 5-methylaminomethyluracil,5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,5′-methoxycarboxymethyluracil, 5-methoxyuracil,2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v),wybutoxosine, pseudouracil, queosine, 2-thiocytosine,5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil,uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v),5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w,and 2,6-diaminopurine.

The antisense oligonucleotide can also comprise at least one modifiedsugar moiety selected from the group including but not limited toarabinose, 2-fluoroarabinose, xylulose, and hexose.

In yet another embodiment, the antisense oligonucleotide will compriseat least one modified phosphate backbone selected from the groupconsisting of a phosphorothioate, a phosphorodithioate, aphosphoramidothioate, a phosphoramidate, a phosphordiamidate, amethylphosphonate, an alkyl phosphotriester, and a formacetal or analogthereof.

In yet another embodiment, the antisense oligonucleotide is anα-anomeric oligonucleotide. An α-anomeric oligonucleotide forms specificdouble-stranded hybrids with complementary RNA in which, contrary to theusual β-units, the strands run parallel to each other (Gautier et al.,1987, Nucl. Acids Res. 15:6625-6641). The oligonucleotide is a2′-O-methylribonucleotide (Inoue et al., 1987, Nucl. Acids Res.15:6131-6148), or a chimeric RNA-DNA analogue (Inoue et al., 1987, FEBSLett. 215:327-330). Alternatively, double stranded RNA can be used todisrupt the expression and function of a targeted NHP.

Oligonucleotides of the invention can be synthesized by standard methodsknown in the art, e.g. by use of an automated DNA synthesizer (such asare commercially available from Biosearch, Applied Biosystems, etc.). Asexamples, phosphorothioate oligonucleotides can be synthesized by themethod of Stein et al. (1988, Nucl. Acids Res. 16:3209), andmethylphosphonate oligonucleotides can be prepared by use of controlledpore glass polymer supports (Sarin et al., 1988, Proc. Natl. Acad. Sci.U.S.A. 85:7448-7451), etc.

Low stringency conditions are well known to those of skill in the art,and will vary predictably depending on the specific organisms from whichthe library and the labeled sequences are derived. For guidanceregarding such conditions see, for example, Sambrook et al., 1989,Molecular Cloning, A Laboratory Manual (and periodic updates thereof),Cold Springs Harbor Press, N.Y.; and Ausubel et al., 1989, CurrentProtocols in Molecular Biology, Green Publishing Associates and WileyInterscience, N.Y.

Alternatively, suitably labeled NHP nucleotide probes can be used toscreen a human genomic library using appropriately stringent conditionsor by PCR. The identification and characterization of human genomicclones is helpful for identifying polymorphisms (including, but notlimited to, nucleotide repeats, microsatellite alleles, singlenucleotide polymorphisms, or coding single nucleotide polymorphisms),determining the genomic structure of a given locus/allele, and designingdiagnostic tests. For example, sequences derived from regions adjacentto the intron/exon boundaries of the human gene can be used to designprimers for use in amplification assays to detect mutations within theexons, introns, splice sites (e.g., splice acceptor and/or donor sites),etc., that can be used in diagnostics and pharmacogenomics.

Further, a NHP gene homolog can be isolated from nucleic acid from anorganism of interest by performing PCR using two degenerate or “wobble”oligonucleotide primer pools designed on the basis of amino acidsequences within the NHP products disclosed herein. The template for thereaction may be total RNA, mRNA, and/or cDNA obtained by reversetranscription of mRNA prepared from human or non-human cell lines ortissue known or suspected to express an allele of a NHP gene. The PCRproduct can be subcloned and sequenced to ensure that the amplifiedsequences represent the sequence of the desired NHP gene. The PCRfragment can then be used to isolate a full length cDNA clone by avariety of methods. For example, the amplified fragment can be labeledand used to screen a cDNA library, such as a bacteriophage cDNA library.Alternatively, the labeled fragment can be used to isolate genomicclones via the screening of a genomic library.

PCR technology can also be used to isolate full length cDNA sequences.For example, RNA can be isolated, following standard procedures, from anappropriate cellular or tissue source (i.e., one known, or suspected, toexpress a NHP gene). A reverse transcription (RT) reaction can beperformed on the RNA using an oligonucleotide primer specific for themost 5′ end of the amplified fragment for the priming of first strandsynthesis. The resulting RNA/DNA hybrid may then be “tailed” using astandard terminal transferase reaction, the hybrid may be digested withRNase H, and second strand synthesis may then be primed with acomplementary primer. Thus, cDNA sequences upstream of the amplifiedfragment can be isolated. For a review of cloning strategies that can beused, see e.g., Sambrook et al., 1989, supra.

A cDNA encoding a mutant NHP gene can be isolated, for example, by usingPCR. In this case, the first cDNA strand may be synthesized byhybridizing an oligo-dT oligonucleotide to mRNA isolated from tissueknown or suspected to be expressed in an individual putatively carryinga mutant NHP allele, and by extending the new strand with reversetranscriptase. The second strand of the cDNA is then synthesized usingan oligonucleotide that hybridizes specifically to the 5′ end of thenormal gene. Using these two primers, the product is then amplified viaPCR, optionally cloned into a suitable vector, and subjected to DNAsequence analysis through methods well known to those of skill in theart. By comparing the DNA sequence of the mutant NHP allele to that of acorresponding normal NHP allele, the mutation(s) responsible for theloss or alteration of function of the mutant NHP gene product can beascertained.

Alternatively, a genomic library can be constructed using DNA obtainedfrom an individual suspected of or known to carry a mutant NHP allele(e.g., a person manifesting a NHP-associated phenotype such as, forexample, obesity, high blood pressure, connective tissue disorders,infertility, etc.), or a cDNA library can be constructed using RNA froma tissue known, or suspected, to express a mutant NHP allele. A normalNHP gene, or any suitable fragment thereof, can then be labeled and usedas a probe to identify the corresponding mutant NHP allele in suchlibraries. Clones containing mutant NHP gene sequences can then bepurified and subjected to sequence analysis according to methods wellknown to those skilled in the art.

Additionally, an expression library can be constructed utilizing cDNAsynthesized from, for example, RNA isolated from a tissue known, orsuspected, to express a mutant NHP allele in an individual suspected ofor known to carry such a mutant allele. In this manner, gene productsmade by the putatively mutant tissue can be expressed and screened usingstandard antibody screening techniques in conjunction with antibodiesraised against a normal NHP product, as described below. (For screeningtechniques, see, for example, Harlow, E. and Lane, eds., 1988,“Antibodies: A Laboratory Manual”, Cold Spring Harbor Press, Cold SpringHarbor.)

Additionally, screening can be accomplished by screening with labeledNHP fusion proteins, such as, for example, alkaline phosphatase-NHP orNHP-alkaline phosphatase fusion proteins. In cases where a NHP mutationresults in an expressed gene product with altered function (e.g., as aresult of a missense or a frameshift mutation), polyclonal antibodies toa NHP are likely to cross-react with a corresponding mutant NHP geneproduct. Library clones detected via their reaction with such labeledantibodies can be purified and subjected to sequence analysis accordingto methods well known in the art.

The invention also encompasses (a) DNA vectors that contain any of theforegoing NHP coding sequences and/or their complements (i.e.,antisense); (b) DNA expression vectors that contain any of the foregoingNHP coding sequences operatively associated with a regulatory elementthat directs the expression of the coding sequences (for example, baculovirus as described in U.S. Pat. No. 5,869,336 herein incorporated byreference); (c) genetically engineered host cells that contain any ofthe foregoing NHP coding sequences operatively associated with aregulatory element that directs the expression of the coding sequencesin the host cell; and (d) genetically engineered host cells that expressan endogenous NHP gene under the control of an exogenously introducedregulatory element (i.e., gene activation). As used herein, regulatoryelements include, but are not limited to, inducible and non-induciblepromoters, enhancers, operators and other elements known to thoseskilled in the art that drive and regulate expression. Such regulatoryelements include but are not limited to the human cytomegalovirus (hCMV)immediate early gene, regulatable, viral elements (particularlyretroviral LTR promoters), the early or late promoters of SV40adenovirus, the lac system, the trp system, the TAC system, the TRCsystem, the major operator and promoter regions of phage lambda, thecontrol regions of fd coat protein, the promoter for 3-phosphoglyceratekinase (PGK), the promoters of acid phosphatase, and the promoters ofthe yeast α-mating factors.

The present invention also encompasses antibodies and anti-idiotypicantibodies (including Fab fragments), antagonists and agonists of theNHP, as well as compounds or nucleotide constructs that inhibitexpression of a NHP gene (transcription factor inhibitors, antisense andribozyme molecules, or gene or regulatory sequence replacementconstructs), or promote the expression of a NHP (e.g., expressionconstructs in which NHP coding sequences are operatively associated withexpression control elements such as promoters, promoter/enhancers,etc.).

The NHPs or NHP peptides, NHP fusion proteins, NHP nucleotide sequences,antibodies, antagonists and agonists can be useful for the detection ofmutant NHPs or inappropriately expressed NHPs for the diagnosis ofdisease. The NHP proteins or peptides, NHP fusion proteins, NHPnucleotide sequences, host cell expression systems, antibodies,antagonists, agonists and genetically engineered cells and animals canbe used for screening for drugs (or high throughput screening ofcombinatorial libraries) effective in the treatment of the symptomaticor phenotypic manifestations of perturbing the normal function of NHP inthe body. The use of engineered host cells and/or animals may offer anadvantage in that such systems allow not only for the identification ofcompounds that bind to the endogenous receptor for an NHP, but can alsoidentify compounds that trigger NHP-mediated activities or pathways.

Finally, the NHP products can be used as therapeutics. For example,soluble derivatives such as NHP peptides/domains corresponding the NHPs,NHP fusion protein products (especially NHP-Ig fusion proteins, i.e.,fusions of a NHP, or a domain of a NHP, to an IgFc), NHP antibodies andanti-idiotypic antibodies (including Fab fragments), antagonists oragonists (including compounds that modulate or act on downstream targetsin a NHP-mediated pathway) can be used to directly treat diseases ordisorders. For instance, the administration of an effective amount ofsoluble NHP, or a NHP-IgFc fusion protein or an anti-idiotypic antibody(or its Fab) that mimics the NHP could activate or effectivelyantagonize the endogenous NHP receptor. Nucleotide constructs encodingsuch NHP products can be used to genetically engineer host cells toexpress such products in vivo; these genetically engineered cellsfunction as “bioreactors” in the body delivering a continuous supply ofa NHP, a NHP peptide, or a NHP fusion protein to the body. Nucleotideconstructs encoding functional NHPs, mutant NHPs, as well as antisenseand ribozyme molecules can also be used in “gene therapy” approaches forthe modulation of NHP expression. Thus, the invention also encompassespharmaceutical formulations and methods for treating biologicaldisorders.

Various aspects of the invention are described in greater detail in thesubsections below.

5.1 The NHP Sequences

The cDNA sequences and the corresponding deduced amino acid sequences ofthe described NHPs are presented in the Sequence Listing. The NHPnucleotides were obtained from clustered human gene trapped sequences,ESTs and a human placenta cDNA library (Edge Biosystems, Gaithersburg,Md.). The described sequences share structural similarity with calciumtransporting ATPases and aminophospholipid transporters.

5.2 NHPS and NHP Polypeptides

NHPs, polypeptides, peptide fragments, mutated, truncated, or deletedforms of the NHPs, and/or NHP fusion proteins can be prepared for avariety of uses. These uses include, but are not limited to, thegeneration of antibodies, as reagents in diagnostic assays, for theidentification of other cellular gene products related to a NHP, asreagents in assays for screening for compounds that can be aspharmaceutical reagents useful in the therapeutic treatment of mental,biological, or medical disorders and disease. Given the similarityinformation and expression data, the described NHPs can be targeted (bydrugs, oligos, antibodies, etc,) in order to treat disease, or totherapeutically augment the efficacy of therapeutic agents.

The Sequence Listing discloses the amino acid sequences encoded by thedescribed NHP genes. The NHPs typically display initiator methionines inDNA sequence contexts consistent with a translation initiation site.

The NHP amino acid sequences of the invention include the amino acidsequence presented in the Sequence Listing as well as analogues andderivatives thereof. Further, corresponding NHP homologues from otherspecies are encompassed by the invention. In fact, any NHP proteinencoded by the NHP nucleotide sequences described above are within thescope of the invention, as are any novel polynucleotide sequencesencoding all or any novel portion of an amino acid sequence presented inthe Sequence Listing. The degenerate nature of the genetic code is wellknown, and, accordingly, each amino acid presented in the SequenceListing, is generically representative of the well known nucleic acid“triplet” codon, or in many cases codons, that can encode the aminoacid. As such, as contemplated herein, the amino acid sequencespresented in the Sequence Listing, when taken together with the geneticcode (see, for example, Table 4-1 at page 109 of “Molecular CellBiology”, 1986, J. Darnell et al. eds., Scientific American Books, NewYork, N.Y., herein incorporated by reference) are genericallyrepresentative of all the various permutations and combinations ofnucleic acid sequences that can encode such amino acid sequences.

The invention also encompasses proteins that are functionally equivalentto the NHPs encoded by the presently described nucleotide sequences asjudged by any of a number of criteria, including, but not limited to,the ability to bind and cleave a substrate of a NHP, or the ability toeffect an identical or complementary downstream pathway, or a change incellular metabolism (e.g., proteolytic activity, ion flux, tyrosinephosphorylation, transport, etc.). Such functionally equivalent NHPproteins include, but are not limited to, additions or substitutions ofamino acid residues within the amino acid sequence encoded by the NHPnucleotide sequences described above, but which result in a silentchange, thus producing a functionally equivalent gene product. Aminoacid substitutions may be made on the basis of similarity in polarity,charge, solubility, hydrophobicity, hydrophilicity, and/or theamphipathic nature of the residues involved. For example, nonpolar(hydrophobic) amino acids include alanine, leucine, isoleucine, valine,proline, phenylalanine, tryptophan, and methionine; polar neutral aminoacids include glycine, serine, threonine, cysteine, tyrosine,asparagine, and glutamine; positively charged (basic) amino acidsinclude arginine, lysine, and histidine; and negatively charged (acidic)amino acids include aspartic acid and glutamic acid.

A variety of host-expression vector systems can be used to express theNHP nucleotide sequences of the invention. Where, as in the presentinstance, the NHP peptide or polypeptide is thought to be membraneprotein, the hydrophobic regions of the protein can be excised and theresulting soluble peptide or polypeptide can be recovered from theculture media. Such expression systems also encompass engineered hostcells that express a NHP, or functional equivalent, in situ.Purification or enrichment of a NHP from such expression systems can beaccomplished using appropriate detergents and lipid micelles and methodswell known to those skilled in the art. However, such engineered hostcells themselves may be used in situations where it is important notonly to retain the structural and functional characteristics of the NHP,but to assess biological activity, e.g., in drug screening assays.

The expression systems that may be used for purposes of the inventioninclude but are not limited to microorganisms such as bacteria (e.g., E.coli, B. subtilis) transformed with recombinant bacteriophage DNA,plasmid DNA or cosmid DNA expression vectors containing NHP nucleotidesequences; yeast (e.g., Saccharomyces, Pichia) transformed withrecombinant yeast expression vectors containing NHP nucleotidesequences; insect cell systems infected with recombinant virusexpression vectors (e.g., baculovirus) containing NHP sequences; plantcell systems infected with recombinant virus expression vectors (e.g.,cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) ortransformed with recombinant plasmid expression vectors (e.g., Tiplasmid) containing NHP nucleotide sequences; or mammalian cell systems(e.g., COS, CHO, BHK, 293, 3T3) harboring recombinant expressionconstructs containing promoters derived from the genome of mammaliancells (e.g., metallothionein promoter) or from mammalian viruses (e.g.,the adenovirus late promoter; the vaccinia virus 7.5K promoter).

In bacterial systems, a number of expression vectors may beadvantageously selected depending upon the use intended for the NHPproduct being expressed. For example, when a large quantity of such aprotein is to be produced for the generation of pharmaceuticalcompositions of or containing NHP, or for raising antibodies to a NHP,vectors that direct the expression of high levels of fusion proteinproducts that are readily purified may be desirable. Such vectorsinclude, but are not limited, to the E. coli expression vector pUR278(Ruther et al., 1983, EMBO J. 2:1791), in which a NHP coding sequencemay be ligated individually into the vector in frame with the lacZcoding region so that a fusion protein is produced; pIN vectors (Inouye& Inouye, 1985, Nucleic Acids Res. 13:3101-3109; Van Heeke & Schuster,1989, J. Biol. Chem. 264:5503-5509); and the like. pGEX vectors(Pharmacia or American Type Culture Collection) can also be used toexpress foreign polypeptides as fusion proteins with glutathioneS-transferase (GST) . In general, such fusion proteins are soluble andcan easily be purified from lysed cells by adsorption toglutathione-agarose beads followed by elution in the presence of freeglutathione. The PGEX vectors are designed to include thrombin or factorXa protease cleavage sites so that the cloned target gene product can bereleased from the GST moiety.

In an insect system, Autographa californica nuclear polyhidrosis virus(AcNPV) is used as a vector to express foreign genes. The virus grows inSpodoptera frugiperda cells. A NHP gene coding sequence may be clonedindividually into non-essential regions (for example the polyhedringene) of the virus and placed under control of an AcNPV promoter (forexample the polyhedrin promoter). Successful insertion of NHP genecoding sequence will result in inactivation of the polyhedrin gene andproduction of non-occluded recombinant virus (i.e., virus lacking theproteinaceous coat coded for by the polyhedrin gene). These recombinantviruses are then used to infect Spodoptera frugiperda cells in which theinserted gene is expressed (e.g., see Smith et al., 1983, J. Virol.46:584; Smith, U.S. Pat. No. 4,215,051).

In mammalian host cells, a number of viral-based expression systems maybe utilized. In cases where an adenovirus is used as an expressionvector, the NHP nucleotide sequence of interest may be ligated to anadenovirus transcription/translation control complex, e.g., the latepromoter and tripartite leader sequence. This chimeric gene may then beinserted in the adenovirus genome by in vitro or in vivo recombination.Insertion in a non-essential region of the viral genome (e.g., region E1or E3) will result in a recombinant virus that is viable and capable ofexpressing a NHP product in infected hosts (e.g., See Logan & Shenk,1984, Proc. Natl. Acad. Sci. USA 81:3655-3659). Specific initiationsignals may also be required for efficient translation of inserted NHPnucleotide sequences. These signals include the ATG initiation codon andadjacent sequences. In cases where an entire NHP gene or cDNA, includingits own initiation codon and adjacent sequences, is inserted into theappropriate expression vector, no additional translational controlsignals may be needed. However, in cases where only a portion of a NHPcoding sequence is inserted, exogenous translational control signals,including, perhaps, the ATG initiation codon, must be provided.Furthermore, the initiation codon must be in phase with the readingframe of the desired coding sequence to ensure translation of the entireinsert. These exogenous translational control signals and initiationcodons can be of a variety of origins, both natural and synthetic. Theefficiency of expression may be enhanced by the inclusion of appropriatetranscription enhancer elements, transcription terminators, etc. (SeeBittner et al., 1987, Methods in Enzymol. 153:516-544).

In addition, a host cell strain may be chosen that modulates theexpression of the inserted sequences, or modifies and processes the geneproduct in the specific fashion desired. Such modifications (e.g.,glycosylation) and processing (e.g., cleavage) of protein products maybe important for the function of the protein. Different host cells havecharacteristic and specific mechanisms for the post-translationalprocessing and modification of proteins and gene products. Appropriatecell lines or host systems can be chosen to ensure the correctmodification and processing of the foreign protein expressed. To thisend, eukaryotic host cells which possess the cellular machinery forproper processing of the primary transcript, glycosylation, andphosphorylation of the gene product may be used. Such mammalian hostcells include, but are not limited to, CHO, VERO, BHK, HeLa, COS, MDCK,293, 3T3, WI38, and in particular, human cell lines.

For long-term, high-yield production of recombinant proteins, stableexpression is preferred. For example, cell lines which stably expressthe NHP sequences described above can be engineered. Rather than usingexpression vectors which contain viral origins of replication, hostcells can be transformed with DNA controlled by appropriate expressioncontrol elements (e.g., promoter, enhancer sequences, transcriptionterminators, polyadenylation sites, etc.), and a selectable marker.Following the introduction of the foreign DNA, engineered cells may beallowed to grow for 1-2 days in an enriched media, and then are switchedto a selective media. The selectable marker in the recombinant plasmidconfers resistance to the selection and allows cells to stably integratethe plasmid into their chromosomes and grow to form foci which in turncan be cloned and expanded into cell lines. This method mayadvantageously be used to engineer cell lines which express the NHPproduct. Such engineered cell lines may be particularly useful inscreening and evaluation of compounds that affect the endogenousactivity of the NHP product.

A number of selection systems may be used, including but not limited tothe herpes simplex virus thymidine kinase (Wigler, et al., 1977, Cell11:223), hypoxanthine-guanine phosphoribosyltransferase (Szybalska &Szybalski, 1962, Proc. Natl. Acad. Sci. USA 48:2026), and adeninephosphoribosyltransferase (Lowy, et al., 1980, Cell 22:817) genes can beemployed in tk⁻, hgprt⁻ or aprt⁻ cells, respectively. Also,antimetabolite resistance can be used as the basis of selection for thefollowing genes: dhfr, which confers resistance to methotrexate (Wigler,et al., 1980, Natl. Acad. Sci. USA 77:3567; O'Hare, et al., 1981, Proc.Natl. Acad. Sci. USA 78:1527); gpt, which confers resistance tomycophenolic acid (Mulligan & Berg, 1981, Proc. Natl. Acad. Sci. USA78:2072); neo, which confers resistance to the aminoglycoside G-418(Colberre-Garapin, et al., 1981, J. Mol. Biol. 150:1); and hygro, whichconfers resistance to hygromycin (Santerre, et al., 1984, Gene 30:147).

Alternatively, any fusion protein can be readily purified by utilizingan antibody specific for the fusion protein being expressed. Forexample, a system described by Janknecht et al. allows for the readypurification of non-denatured fusion proteins expressed in human celllines (Janknecht, et al., 1991, Proc. Natl. Acad. Sci. USA88:8972-8976). In this system, the gene of interest is subcloned into avaccinia recombination plasmid such that the gene's open reading frameis translationally fused to an amino-terminal tag consisting of sixhistidine residues. Extracts from cells infected with recombinantvaccinia virus are loaded onto Ni²⁺.nitriloacetic acid-agarose columnsand histidine-tagged proteins are selectively eluted withimidazole-containing buffers.

5.3 Antibodies to NHP Products

Antibodies that specifically recognize one or more epitopes of a NHP, orepitopes of conserved variants of a NHP, or peptide fragments of a NHPare also encompassed by the invention. Such antibodies include but arenot limited to polyclonal antibodies, monoclonal antibodies (mAbs),humanized or chimeric antibodies, single chain antibodies, Fabfragments, F(ab′)₂ fragments, fragments produced by a Fab expressionlibrary, anti-idiotypic (anti-Id) antibodies, and epitope-bindingfragments of any of the above.

The antibodies of the invention may be used, for example, in thedetection of NHP in a biological sample and may, therefore, be utilizedas part of a diagnostic or prognostic technique whereby patients may betested for abnormal amounts of NHP. Such antibodies may also be utilizedin conjunction with, for example, compound screening schemes for theevaluation of the effect of test compounds on expression and/or activityof a NHP gene product. Additionally, such antibodies can be used inconjunction gene therapy to, for example, evaluate the normal and/orengineered NHP-expressing cells prior to their introduction into thepatient. Such antibodies may additionally be used as a method for theinhibition of abnormal NHP activity. Thus, such antibodies may,therefore, be utilized as part of treatment methods.

For the production of antibodies, various host animals may be immunizedby injection with the NHP, an NHP peptide (e.g., one corresponding the afunctional domain of an NHP), truncated NHP polypeptides (NHP in whichone or more domains have been deleted), functional equivalents of theNHP or mutated variant of the NHP. Such host animals may include but arenot limited to pigs, rabbits, mice, goats, and rats, to name but a few.Various adjuvants may be used to increase the immunological response,depending on the host species, including but not limited to Freund'sadjuvant (complete and incomplete), mineral salts such as aluminumhydroxide or aluminum phosphate, surface active substances such aslysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, andpotentially useful human adjuvants such as BCG (bacille Calmette-Guerin)and Corynebacterium parvum. Alternatively, the immune response could beenhanced by combination and or coupling with molecules such as keyholelimpet hemocyanin, tetanus toxoid, diptheria toxoid, ovalbumin, choleratoxin or fragments thereof. Polyclonal antibodies are heterogeneouspopulations of antibody molecules derived from the sera of the immunizedanimals.

Monoclonal antibodies, which are homogeneous populations of antibodiesto a particular antigen, can be obtained by any technique which providesfor the production of antibody molecules by continuous cell lines inculture. These include, but are not limited to, the hybridoma techniqueof Kohler and Milstein, (1975, Nature 256:495-497; and U.S. Pat. No.4,376,110), the human B-cell hybridoma technique (Kosbor et al., 1983,Immunology Today 4:72; Cole et al., 1983, Proc. Natl. Acad. Sci. USA80:2026-2030), and the EBV-hybridoma technique (Cole et al., 1985,Monoclonal Antibodies And Cancer Therapy, Alan R. Liss, Inc., pp.77-96). Such antibodies may be of any immunoglobulin class includingIgG, IgM, IgE, IgA, IgD and any subclass thereof. The hybridomaproducing the mAb of this invention may be cultivated in vitro or invivo. Production of high titers of mabs in vivo makes this the presentlypreferred method of production.

In addition, techniques developed for the production of “chimericantibodies” (Morrison et al., 1984, Proc. Natl. Acad. Sci.,81:6851-6855; Neuberger et al., 1984, Nature, 312:604-608; Takeda etal., 1985, Nature, 314:452-454) by splicing the genes from a mouseantibody molecule of appropriate antigen specificity together with genesfrom a human antibody molecule of appropriate biological activity can beused. A chimeric antibody is a molecule in which different portions arederived from different animal species, such as those having a variableregion derived from a murine mAb and a human immunoglobulin constantregion. Such technologies are described in U.S. Pat. Nos. 6,075,181 and5,877,397 and their respective disclosures which are herein incorporatedby reference in their entirety.

Alternatively, techniques described for the production of single chainantibodies (U.S. Pat. No. 4,946,778; Bird, 1988, Science 242:423-426;Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; and Wardet al., 1989, Nature 334:544-546) can be adapted to produce single chainantibodies against NHP gene products. Single chain antibodies are formedby linking the heavy and light chain fragments of the Fv region via anamino acid bridge, resulting in a single chain polypeptide.

Antibody fragments which recognize specific epitopes may be generated byknown techniques. For example, such fragments include, but are notlimited to: the F(ab′)₂ fragments which can be produced by pepsindigestion of the antibody molecule and the Fab fragments which can begenerated by reducing the disulfide bridges of the F(ab′)₂ fragments.Alternatively, Fab expression libraries may be constructed (Huse et al.,1989, Science, 246:1275-1281) to allow rapid and easy identification ofmonoclonal Fab fragments with the desired specificity.

Antibodies to a NHP can, in turn, be utilized to generate anti-idiotypeantibodies that “mimic” a given NHP, using techniques well known tothose skilled in the art. (See, e.g., Greenspan & Bona, 1993, FASEB J7(5):437-444; and Nissinoff, 1991, J. Immunol. 147(8):2429-2438). Forexample antibodies which bind to a NHP domain and competitively inhibitthe binding of NHP to its cognate receptor can be used to generateanti-idiotypes that “mimic” the NHP and, therefore, bind and activate orneutralize a receptor. Such anti-idiotypic antibodies or Fab fragmentsof such anti-idiotypes can be used in therapeutic regimens involving aNHP mediated pathway.

The present invention is not to be limited in scope by the specificembodiments described herein, which are intended as single illustrationsof individual aspects of the invention, and functionally equivalentmethods and components are within the scope of the invention. Indeed,various modifications of the invention, in addition to those shown anddescribed herein will become apparent to those skilled in the art fromthe foregoing description. Such modifications are intended to fallwithin the scope of the appended claims. All cited publications,patents, and patent applications are herein incorporated by reference intheir entirety.

17 1 2919 DNA homo sapiens 1 atgactgagg ctctccaatg ggccagatat cactggcgacggctgatcag aggtgcaacc 60 agggatgatg attcagggcc atacaactat tcctcgttgctcgcctgtgg gcgcaagtcc 120 tctcagatcc ctaaactgtc aggaaggcac cggattgttgttccccacat ccagcccttc 180 aaggatgagt atgagaagtt ctccggagcc tatgtgaacaatcgaatacg aacaacaaag 240 tacacacttc tgaattttgt gccaagaaat ttatttgaacaatttcacag agctgccaat 300 ttatatttcc tgttcctagt tgtcctgaac tgggtacctttggtagaagc cttccaaaag 360 gaaatcacca tgttgcctct ggtggtggtc cttacaattatcgcaattaa agatggcctg 420 gaagattatc ggaaatacaa aattgacaaa cagatcaataatttaataac taaagtttat 480 agtaggaaag agaaaaaata cattgaccga tgctggaaagacgttactgt tggggacttt 540 attcgcctct cctgcaacga ggtcatccct gcagacatggtactactctt ttccactgat 600 ccagatggaa tctgtcacat tgagacttct ggtcttgatggagagagcaa tttaaaacag 660 aggcaggtgg ttcggggata tgcagaacag gactctgaagttgatcctga gaagttttcc 720 agtaggatag aatgtgaaag cccaaacaat gacctcagcagattccgagg cttcctagaa 780 cattccaaca aagaacgcgt gggtctcagt aaagaaaatttgttgcttag aggatgcacc 840 attagaaaca cagaggctgt tgtgggcatt gtggtttatgcaggccatga aaccaaagca 900 atgctgaaca acagtgggcc acggtataag cgcagcaaattagaaagaag agcaaacaca 960 gatgtcctct ggtgtgtcat gcttctggtc ataatgtgcttaactggcgc agtaggtcat 1020 ggaatctggc tgagcaggta tgaaaagatg cattttttcaatgttcccga gcctgatgga 1080 catatcatat caccactgtt ggcaggattt tatatgttttggaccatgat cattttgtta 1140 caggtcttga ttcctatttc tctctatgtt tccatcgaaattgtgaagct tggacaaata 1200 tatttcattc aaagtgatgt ggatttctac aatgaaaaaatggattctat tgttcagtgc 1260 cgagccctga acatcgccga ggatctggga cagattcagtacctcttttc cgataagaca 1320 ggaaccctca ctgagaataa gatggttttt cgaagatgtagtgtggcagg atttgattac 1380 tgccatgaag aaaatgccag gaggttggag tcctatcaggaagctgtctc tgaagatgaa 1440 gattttatag acacagtcag tggttccctc agcaatatggcaaaaccgag agcccccagc 1500 tgcaggacag ttcataatgg gcctttggga aataagccctcaaatcatct tgctgggagc 1560 tcttttactc taggaagtgg agaaggagcc agtgaagtgcctcattccag acaggctgct 1620 ttcagtagcc ccattgaaac agacgtggta ccagacaccaggcttttaga caaatttagt 1680 cagattacac ctcggctctt tatgccacta gatgagaccatccaaaatcc accaatggaa 1740 actttgtaca ttatcgactt tttcattgca ttggcaatttgcaacacagt agtggtttct 1800 gctcctaacc aaccccgaca aaagatcaga cacccttcactgggggggtt gcccattaag 1860 tctttggaag agattaaaag tcttttccag agatggtctgtccgaagatc aagttctcca 1920 tcgcttaaca gtgggaaaga gccatcttct ggagttccaaacgcctttgt gagcagactc 1980 cctctcttta gtcgaatgaa accagcttca cctgtggaggaagaggtctc ccaggtgtgt 2040 gagagccccc agtgctccag tagctcagct tgctgcacagaaacagagaa acaacacggt 2100 gatgcaggcc tcctgaatgg caaggcagag tccctccctggacagccatt ggcctgcaac 2160 ctgtgttatg aggccgagag cccagacgaa gcggccttagtgtatgccgc cagggcttac 2220 caatgcactt tacggtctcg gacaccagag caggtcatggtggactttgc tgctttggga 2280 ccattaacat ttcaactcct acacatcctg ccctttgactcagtaagaaa aagaatgtct 2340 gttgtggtcc gacaccctct ttccaatcaa gttgtggtgtatacgaaagg cgctgattct 2400 gtgatcatgg agttactgtc ggtggcttcc ccagatggagcaagtctgga gaaacaacag 2460 atgatagtaa gggagaaaac ccagaagcac ttggatgactatgccaaaca aggccttcgt 2520 actttatgta tagcaaagaa ggtcatgagt gacactgaatatgcagagtg gctgaggaat 2580 cattttttag ctgaaaccag cattgacaac agggaagaattactacttga atctgccatg 2640 aggttggaga acaaacttac attacttggt gctactggcattgaagaccg tctgcaggag 2700 ggagtccctg aatctataga agctcttcac aaagcgggcatcaagatctg gatgctgaca 2760 ggggacaagc aggagacagc tgtcaacata gcttatgcatgcaaactact ggagccagat 2820 gacaagcttt ttatcctcaa tacccaaagt aaagtgcgtatattgagatt aaatctgttc 2880 ttctgtattt tcaaaggcat tggaacattt gagatttga2919 2 972 PRT homo sapiens 2 Met Thr Glu Ala Leu Gln Trp Ala Arg TyrHis Trp Arg Arg Leu Ile 1 5 10 15 Arg Gly Ala Thr Arg Asp Asp Asp SerGly Pro Tyr Asn Tyr Ser Ser 20 25 30 Leu Leu Ala Cys Gly Arg Lys Ser SerGln Ile Pro Lys Leu Ser Gly 35 40 45 Arg His Arg Ile Val Val Pro His IleGln Pro Phe Lys Asp Glu Tyr 50 55 60 Glu Lys Phe Ser Gly Ala Tyr Val AsnAsn Arg Ile Arg Thr Thr Lys 65 70 75 80 Tyr Thr Leu Leu Asn Phe Val ProArg Asn Leu Phe Glu Gln Phe His 85 90 95 Arg Ala Ala Asn Leu Tyr Phe LeuPhe Leu Val Val Leu Asn Trp Val 100 105 110 Pro Leu Val Glu Ala Phe GlnLys Glu Ile Thr Met Leu Pro Leu Val 115 120 125 Val Val Leu Thr Ile IleAla Ile Lys Asp Gly Leu Glu Asp Tyr Arg 130 135 140 Lys Tyr Lys Ile AspLys Gln Ile Asn Asn Leu Ile Thr Lys Val Tyr 145 150 155 160 Ser Arg LysGlu Lys Lys Tyr Ile Asp Arg Cys Trp Lys Asp Val Thr 165 170 175 Val GlyAsp Phe Ile Arg Leu Ser Cys Asn Glu Val Ile Pro Ala Asp 180 185 190 MetVal Leu Leu Phe Ser Thr Asp Pro Asp Gly Ile Cys His Ile Glu 195 200 205Thr Ser Gly Leu Asp Gly Glu Ser Asn Leu Lys Gln Arg Gln Val Val 210 215220 Arg Gly Tyr Ala Glu Gln Asp Ser Glu Val Asp Pro Glu Lys Phe Ser 225230 235 240 Ser Arg Ile Glu Cys Glu Ser Pro Asn Asn Asp Leu Ser Arg PheArg 245 250 255 Gly Phe Leu Glu His Ser Asn Lys Glu Arg Val Gly Leu SerLys Glu 260 265 270 Asn Leu Leu Leu Arg Gly Cys Thr Ile Arg Asn Thr GluAla Val Val 275 280 285 Gly Ile Val Val Tyr Ala Gly His Glu Thr Lys AlaMet Leu Asn Asn 290 295 300 Ser Gly Pro Arg Tyr Lys Arg Ser Lys Leu GluArg Arg Ala Asn Thr 305 310 315 320 Asp Val Leu Trp Cys Val Met Leu LeuVal Ile Met Cys Leu Thr Gly 325 330 335 Ala Val Gly His Gly Ile Trp LeuSer Arg Tyr Glu Lys Met His Phe 340 345 350 Phe Asn Val Pro Glu Pro AspGly His Ile Ile Ser Pro Leu Leu Ala 355 360 365 Gly Phe Tyr Met Phe TrpThr Met Ile Ile Leu Leu Gln Val Leu Ile 370 375 380 Pro Ile Ser Leu TyrVal Ser Ile Glu Ile Val Lys Leu Gly Gln Ile 385 390 395 400 Tyr Phe IleGln Ser Asp Val Asp Phe Tyr Asn Glu Lys Met Asp Ser 405 410 415 Ile ValGln Cys Arg Ala Leu Asn Ile Ala Glu Asp Leu Gly Gln Ile 420 425 430 GlnTyr Leu Phe Ser Asp Lys Thr Gly Thr Leu Thr Glu Asn Lys Met 435 440 445Val Phe Arg Arg Cys Ser Val Ala Gly Phe Asp Tyr Cys His Glu Glu 450 455460 Asn Ala Arg Arg Leu Glu Ser Tyr Gln Glu Ala Val Ser Glu Asp Glu 465470 475 480 Asp Phe Ile Asp Thr Val Ser Gly Ser Leu Ser Asn Met Ala LysPro 485 490 495 Arg Ala Pro Ser Cys Arg Thr Val His Asn Gly Pro Leu GlyAsn Lys 500 505 510 Pro Ser Asn His Leu Ala Gly Ser Ser Phe Thr Leu GlySer Gly Glu 515 520 525 Gly Ala Ser Glu Val Pro His Ser Arg Gln Ala AlaPhe Ser Ser Pro 530 535 540 Ile Glu Thr Asp Val Val Pro Asp Thr Arg LeuLeu Asp Lys Phe Ser 545 550 555 560 Gln Ile Thr Pro Arg Leu Phe Met ProLeu Asp Glu Thr Ile Gln Asn 565 570 575 Pro Pro Met Glu Thr Leu Tyr IleIle Asp Phe Phe Ile Ala Leu Ala 580 585 590 Ile Cys Asn Thr Val Val ValSer Ala Pro Asn Gln Pro Arg Gln Lys 595 600 605 Ile Arg His Pro Ser LeuGly Gly Leu Pro Ile Lys Ser Leu Glu Glu 610 615 620 Ile Lys Ser Leu PheGln Arg Trp Ser Val Arg Arg Ser Ser Ser Pro 625 630 635 640 Ser Leu AsnSer Gly Lys Glu Pro Ser Ser Gly Val Pro Asn Ala Phe 645 650 655 Val SerArg Leu Pro Leu Phe Ser Arg Met Lys Pro Ala Ser Pro Val 660 665 670 GluGlu Glu Val Ser Gln Val Cys Glu Ser Pro Gln Cys Ser Ser Ser 675 680 685Ser Ala Cys Cys Thr Glu Thr Glu Lys Gln His Gly Asp Ala Gly Leu 690 695700 Leu Asn Gly Lys Ala Glu Ser Leu Pro Gly Gln Pro Leu Ala Cys Asn 705710 715 720 Leu Cys Tyr Glu Ala Glu Ser Pro Asp Glu Ala Ala Leu Val TyrAla 725 730 735 Ala Arg Ala Tyr Gln Cys Thr Leu Arg Ser Arg Thr Pro GluGln Val 740 745 750 Met Val Asp Phe Ala Ala Leu Gly Pro Leu Thr Phe GlnLeu Leu His 755 760 765 Ile Leu Pro Phe Asp Ser Val Arg Lys Arg Met SerVal Val Val Arg 770 775 780 His Pro Leu Ser Asn Gln Val Val Val Tyr ThrLys Gly Ala Asp Ser 785 790 795 800 Val Ile Met Glu Leu Leu Ser Val AlaSer Pro Asp Gly Ala Ser Leu 805 810 815 Glu Lys Gln Gln Met Ile Val ArgGlu Lys Thr Gln Lys His Leu Asp 820 825 830 Asp Tyr Ala Lys Gln Gly LeuArg Thr Leu Cys Ile Ala Lys Lys Val 835 840 845 Met Ser Asp Thr Glu TyrAla Glu Trp Leu Arg Asn His Phe Leu Ala 850 855 860 Glu Thr Ser Ile AspAsn Arg Glu Glu Leu Leu Leu Glu Ser Ala Met 865 870 875 880 Arg Leu GluAsn Lys Leu Thr Leu Leu Gly Ala Thr Gly Ile Glu Asp 885 890 895 Arg LeuGln Glu Gly Val Pro Glu Ser Ile Glu Ala Leu His Lys Ala 900 905 910 GlyIle Lys Ile Trp Met Leu Thr Gly Asp Lys Gln Glu Thr Ala Val 915 920 925Asn Ile Ala Tyr Ala Cys Lys Leu Leu Glu Pro Asp Asp Lys Leu Phe 930 935940 Ile Leu Asn Thr Gln Ser Lys Val Arg Ile Leu Arg Leu Asn Leu Phe 945950 955 960 Phe Cys Ile Phe Lys Gly Ile Gly Thr Phe Glu Ile 965 970 3375 DNA homo sapiens 3 atgagtgaca ctgaatatgc agagtggctg aggaatcattttttagctga aaccagcatt 60 gacaacaggg aagaattact acttgaatct gccatgaggttggagaacaa acttacatta 120 cttggtgcta ctggcattga agaccgtctg caggagggagtccctgaatc tatagaagct 180 cttcacaaag cgggcatcaa gatctggatg ctgacaggggacaagcagga gacagctgtc 240 aacatagctt atgcatgcaa actactggag ccagatgacaagctttttat cctcaatacc 300 caaagtaaag tgcgtatatt gagattaaat ctgttcttctgtattttcaa aggcattgga 360 acatttgaga tttga 375 4 124 PRT homo sapiens 4Met Ser Asp Thr Glu Tyr Ala Glu Trp Leu Arg Asn His Phe Leu Ala 1 5 1015 Glu Thr Ser Ile Asp Asn Arg Glu Glu Leu Leu Leu Glu Ser Ala Met 20 2530 Arg Leu Glu Asn Lys Leu Thr Leu Leu Gly Ala Thr Gly Ile Glu Asp 35 4045 Arg Leu Gln Glu Gly Val Pro Glu Ser Ile Glu Ala Leu His Lys Ala 50 5560 Gly Ile Lys Ile Trp Met Leu Thr Gly Asp Lys Gln Glu Thr Ala Val 65 7075 80 Asn Ile Ala Tyr Ala Cys Lys Leu Leu Glu Pro Asp Asp Lys Leu Phe 8590 95 Ile Leu Asn Thr Gln Ser Lys Val Arg Ile Leu Arg Leu Asn Leu Phe100 105 110 Phe Cys Ile Phe Lys Gly Ile Gly Thr Phe Glu Ile 115 120 53171 DNA homo sapiens 5 atgactgagg ctctccaatg ggccagatat cactggcgacggctgatcag aggtgcaacc 60 agggatgatg attcagggcc atacaactat tcctcgttgctcgcctgtgg gcgcaagtcc 120 tctcagatcc ctaaactgtc aggaaggcac cggattgttgttccccacat ccagcccttc 180 aaggatgagt atgagaagtt ctccggagcc tatgtgaacaatcgaatacg aacaacaaag 240 tacacacttc tgaattttgt gccaagaaat ttatttgaacaatttcacag agctgccaat 300 ttatatttcc tgttcctagt tgtcctgaac tgggtacctttggtagaagc cttccaaaag 360 gaaatcacca tgttgcctct ggtggtggtc cttacaattatcgcaattaa agatggcctg 420 gaagattatc ggaaatacaa aattgacaaa cagatcaataatttaataac taaagtttat 480 agtaggaaag agaaaaaata cattgaccga tgctggaaagacgttactgt tggggacttt 540 attcgcctct cctgcaacga ggtcatccct gcagacatggtactactctt ttccactgat 600 ccagatggaa tctgtcacat tgagacttct ggtcttgatggagagagcaa tttaaaacag 660 aggcaggtgg ttcggggata tgcagaacag gactctgaagttgatcctga gaagttttcc 720 agtaggatag aatgtgaaag cccaaacaat gacctcagcagattccgagg cttcctagaa 780 cattccaaca aagaacgcgt gggtctcagt aaagaaaatttgttgcttag aggatgcacc 840 attagaaaca cagaggctgt tgtgggcatt gtggtttatgcaggccatga aaccaaagca 900 atgctgaaca acagtgggcc acggtataag cgcagcaaattagaaagaag agcaaacaca 960 gatgtcctct ggtgtgtcat gcttctggtc ataatgtgcttaactggcgc agtaggtcat 1020 ggaatctggc tgagcaggta tgaaaagatg cattttttcaatgttcccga gcctgatgga 1080 catatcatat caccactgtt ggcaggattt tatatgttttggaccatgat cattttgtta 1140 caggtcttga ttcctatttc tctctatgtt tccatcgaaattgtgaagct tggacaaata 1200 tatttcattc aaagtgatgt ggatttctac aatgaaaaaatggattctat tgttcagtgc 1260 cgagccctga acatcgccga ggatctggga cagattcagtacctcttttc cgataagaca 1320 ggaaccctca ctgagaataa gatggttttt cgaagatgtagtgtggcagg atttgattac 1380 tgccatgaag aaaatgccag gaggttggag tcctatcaggaagctgtctc tgaagatgaa 1440 gattttatag acacagtcag tggttccctc agcaatatggcaaaaccgag agcccccagc 1500 tgcaggacag ttcataatgg gcctttggga aataagccctcaaatcatct tgctgggagc 1560 tcttttactc taggaagtgg agaaggagcc agtgaagtgcctcattccag acaggctgct 1620 ttcagtagcc ccattgaaac agacgtggta ccagacaccaggcttttaga caaatttagt 1680 cagattacac ctcggctctt tatgccacta gatgagaccatccaaaatcc accaatggaa 1740 actttgtaca ttatcgactt tttcattgca ttggcaatttgcaacacagt agtggtttct 1800 gctcctaacc aaccccgaca aaagatcaga cacccttcactgggggggtt gcccattaag 1860 tctttggaag agattaaaag tcttttccag agatggtctgtccgaagatc aagttctcca 1920 tcgcttaaca gtgggaaaga gccatcttct ggagttccaaacgcctttgt gagcagactc 1980 cctctcttta gtcgaatgaa accagcttca cctgtggaggaagaggtctc ccaggtgtgt 2040 gagagccccc agtgctccag tagctcagct tgctgcacagaaacagagaa acaacacggt 2100 gatgcaggcc tcctgaatgg caaggcagag tccctccctggacagccatt ggcctgcaac 2160 ctgtgttatg aggccgagag cccagacgaa gcggccttagtgtatgccgc cagggcttac 2220 caatgcactt tacggtctcg gacaccagag caggtcatggtggactttgc tgctttggga 2280 ccattaacat ttcaactcct acacatcctg ccctttgactcagtaagaaa aagaatgtct 2340 gttgtggtcc gacaccctct ttccaatcaa gttgtggtgtatacgaaagg cgctgattct 2400 gtgatcatgg agttactgtc ggtggcttcc ccagatggagcaagtctgga gaaacaacag 2460 atgatagtaa gggagaaaac ccagaagcac ttggatgactatgccaaaca aggccttcgt 2520 actttatgta tagcaaagaa ggtcatgagt gacactgaatatgcagagtg gctgaggaat 2580 cattttttag ctgaaaccag cattgacaac agggaagaattactacttga atctgccatg 2640 aggttggaga acaaacttac attacttggt gctactggcattgaagaccg tctgcaggag 2700 ggagtccctg aatctataga agctcttcac aaagcgggcatcaagatctg gatgctgaca 2760 ggggacaagc aggagacagc tgtcaacata gcttatgcatgcaaactact ggagccagat 2820 gacaagcttt ttatcctcaa tacccaaagt aaagatgcctgtgggatgct gatgagcaca 2880 attttgaaag aacttcagaa gaaaactcaa gccctgccagagcaagtgtc attaagtgaa 2940 gatttacttc agcctcctgt cccccgggac tcagggttacgagctggact cattatcact 3000 gggaagaccc tggagtttgc cctgcaagaa agtctgcaaaagcagttcct ggaactgaca 3060 tcttggtgtc aagctgtggt ctgctgccga gccacaccgctgcagaaaag tgaagtggtg 3120 aaattggtcc gcagccatct ccaggtgatg acccttgctattggtgagtg a 3171 6 1056 PRT homo sapiens 6 Met Thr Glu Ala Leu Gln TrpAla Arg Tyr His Trp Arg Arg Leu Ile 1 5 10 15 Arg Gly Ala Thr Arg AspAsp Asp Ser Gly Pro Tyr Asn Tyr Ser Ser 20 25 30 Leu Leu Ala Cys Gly ArgLys Ser Ser Gln Ile Pro Lys Leu Ser Gly 35 40 45 Arg His Arg Ile Val ValPro His Ile Gln Pro Phe Lys Asp Glu Tyr 50 55 60 Glu Lys Phe Ser Gly AlaTyr Val Asn Asn Arg Ile Arg Thr Thr Lys 65 70 75 80 Tyr Thr Leu Leu AsnPhe Val Pro Arg Asn Leu Phe Glu Gln Phe His 85 90 95 Arg Ala Ala Asn LeuTyr Phe Leu Phe Leu Val Val Leu Asn Trp Val 100 105 110 Pro Leu Val GluAla Phe Gln Lys Glu Ile Thr Met Leu Pro Leu Val 115 120 125 Val Val LeuThr Ile Ile Ala Ile Lys Asp Gly Leu Glu Asp Tyr Arg 130 135 140 Lys TyrLys Ile Asp Lys Gln Ile Asn Asn Leu Ile Thr Lys Val Tyr 145 150 155 160Ser Arg Lys Glu Lys Lys Tyr Ile Asp Arg Cys Trp Lys Asp Val Thr 165 170175 Val Gly Asp Phe Ile Arg Leu Ser Cys Asn Glu Val Ile Pro Ala Asp 180185 190 Met Val Leu Leu Phe Ser Thr Asp Pro Asp Gly Ile Cys His Ile Glu195 200 205 Thr Ser Gly Leu Asp Gly Glu Ser Asn Leu Lys Gln Arg Gln ValVal 210 215 220 Arg Gly Tyr Ala Glu Gln Asp Ser Glu Val Asp Pro Glu LysPhe Ser 225 230 235 240 Ser Arg Ile Glu Cys Glu Ser Pro Asn Asn Asp LeuSer Arg Phe Arg 245 250 255 Gly Phe Leu Glu His Ser Asn Lys Glu Arg ValGly Leu Ser Lys Glu 260 265 270 Asn Leu Leu Leu Arg Gly Cys Thr Ile ArgAsn Thr Glu Ala Val Val 275 280 285 Gly Ile Val Val Tyr Ala Gly His GluThr Lys Ala Met Leu Asn Asn 290 295 300 Ser Gly Pro Arg Tyr Lys Arg SerLys Leu Glu Arg Arg Ala Asn Thr 305 310 315 320 Asp Val Leu Trp Cys ValMet Leu Leu Val Ile Met Cys Leu Thr Gly 325 330 335 Ala Val Gly His GlyIle Trp Leu Ser Arg Tyr Glu Lys Met His Phe 340 345 350 Phe Asn Val ProGlu Pro Asp Gly His Ile Ile Ser Pro Leu Leu Ala 355 360 365 Gly Phe TyrMet Phe Trp Thr Met Ile Ile Leu Leu Gln Val Leu Ile 370 375 380 Pro IleSer Leu Tyr Val Ser Ile Glu Ile Val Lys Leu Gly Gln Ile 385 390 395 400Tyr Phe Ile Gln Ser Asp Val Asp Phe Tyr Asn Glu Lys Met Asp Ser 405 410415 Ile Val Gln Cys Arg Ala Leu Asn Ile Ala Glu Asp Leu Gly Gln Ile 420425 430 Gln Tyr Leu Phe Ser Asp Lys Thr Gly Thr Leu Thr Glu Asn Lys Met435 440 445 Val Phe Arg Arg Cys Ser Val Ala Gly Phe Asp Tyr Cys His GluGlu 450 455 460 Asn Ala Arg Arg Leu Glu Ser Tyr Gln Glu Ala Val Ser GluAsp Glu 465 470 475 480 Asp Phe Ile Asp Thr Val Ser Gly Ser Leu Ser AsnMet Ala Lys Pro 485 490 495 Arg Ala Pro Ser Cys Arg Thr Val His Asn GlyPro Leu Gly Asn Lys 500 505 510 Pro Ser Asn His Leu Ala Gly Ser Ser PheThr Leu Gly Ser Gly Glu 515 520 525 Gly Ala Ser Glu Val Pro His Ser ArgGln Ala Ala Phe Ser Ser Pro 530 535 540 Ile Glu Thr Asp Val Val Pro AspThr Arg Leu Leu Asp Lys Phe Ser 545 550 555 560 Gln Ile Thr Pro Arg LeuPhe Met Pro Leu Asp Glu Thr Ile Gln Asn 565 570 575 Pro Pro Met Glu ThrLeu Tyr Ile Ile Asp Phe Phe Ile Ala Leu Ala 580 585 590 Ile Cys Asn ThrVal Val Val Ser Ala Pro Asn Gln Pro Arg Gln Lys 595 600 605 Ile Arg HisPro Ser Leu Gly Gly Leu Pro Ile Lys Ser Leu Glu Glu 610 615 620 Ile LysSer Leu Phe Gln Arg Trp Ser Val Arg Arg Ser Ser Ser Pro 625 630 635 640Ser Leu Asn Ser Gly Lys Glu Pro Ser Ser Gly Val Pro Asn Ala Phe 645 650655 Val Ser Arg Leu Pro Leu Phe Ser Arg Met Lys Pro Ala Ser Pro Val 660665 670 Glu Glu Glu Val Ser Gln Val Cys Glu Ser Pro Gln Cys Ser Ser Ser675 680 685 Ser Ala Cys Cys Thr Glu Thr Glu Lys Gln His Gly Asp Ala GlyLeu 690 695 700 Leu Asn Gly Lys Ala Glu Ser Leu Pro Gly Gln Pro Leu AlaCys Asn 705 710 715 720 Leu Cys Tyr Glu Ala Glu Ser Pro Asp Glu Ala AlaLeu Val Tyr Ala 725 730 735 Ala Arg Ala Tyr Gln Cys Thr Leu Arg Ser ArgThr Pro Glu Gln Val 740 745 750 Met Val Asp Phe Ala Ala Leu Gly Pro LeuThr Phe Gln Leu Leu His 755 760 765 Ile Leu Pro Phe Asp Ser Val Arg LysArg Met Ser Val Val Val Arg 770 775 780 His Pro Leu Ser Asn Gln Val ValVal Tyr Thr Lys Gly Ala Asp Ser 785 790 795 800 Val Ile Met Glu Leu LeuSer Val Ala Ser Pro Asp Gly Ala Ser Leu 805 810 815 Glu Lys Gln Gln MetIle Val Arg Glu Lys Thr Gln Lys His Leu Asp 820 825 830 Asp Tyr Ala LysGln Gly Leu Arg Thr Leu Cys Ile Ala Lys Lys Val 835 840 845 Met Ser AspThr Glu Tyr Ala Glu Trp Leu Arg Asn His Phe Leu Ala 850 855 860 Glu ThrSer Ile Asp Asn Arg Glu Glu Leu Leu Leu Glu Ser Ala Met 865 870 875 880Arg Leu Glu Asn Lys Leu Thr Leu Leu Gly Ala Thr Gly Ile Glu Asp 885 890895 Arg Leu Gln Glu Gly Val Pro Glu Ser Ile Glu Ala Leu His Lys Ala 900905 910 Gly Ile Lys Ile Trp Met Leu Thr Gly Asp Lys Gln Glu Thr Ala Val915 920 925 Asn Ile Ala Tyr Ala Cys Lys Leu Leu Glu Pro Asp Asp Lys LeuPhe 930 935 940 Ile Leu Asn Thr Gln Ser Lys Asp Ala Cys Gly Met Leu MetSer Thr 945 950 955 960 Ile Leu Lys Glu Leu Gln Lys Lys Thr Gln Ala LeuPro Glu Gln Val 965 970 975 Ser Leu Ser Glu Asp Leu Leu Gln Pro Pro ValPro Arg Asp Ser Gly 980 985 990 Leu Arg Ala Gly Leu Ile Ile Thr Gly LysThr Leu Glu Phe Ala Leu 995 1000 1005 Gln Glu Ser Leu Gln Lys Gln PheLeu Glu Leu Thr Ser Trp Cys Gln 1010 1015 1020 Ala Val Val Cys Cys ArgAla Thr Pro Leu Gln Lys Ser Glu Val Val 1025 1030 1035 1040 Lys Leu ValArg Ser His Leu Gln Val Met Thr Leu Ala Ile Gly Glu 1045 1050 1055 7 627DNA homo sapiens 7 atgagtgaca ctgaatatgc agagtggctg aggaatcattttttagctga aaccagcatt 60 gacaacaggg aagaattact acttgaatct gccatgaggttggagaacaa acttacatta 120 cttggtgcta ctggcattga agaccgtctg caggagggagtccctgaatc tatagaagct 180 cttcacaaag cgggcatcaa gatctggatg ctgacaggggacaagcagga gacagctgtc 240 aacatagctt atgcatgcaa actactggag ccagatgacaagctttttat cctcaatacc 300 caaagtaaag atgcctgtgg gatgctgatg agcacaattttgaaagaact tcagaagaaa 360 actcaagccc tgccagagca agtgtcatta agtgaagatttacttcagcc tcctgtcccc 420 cgggactcag ggttacgagc tggactcatt atcactgggaagaccctgga gtttgccctg 480 caagaaagtc tgcaaaagca gttcctggaa ctgacatcttggtgtcaagc tgtggtctgc 540 tgccgagcca caccgctgca gaaaagtgaa gtggtgaaattggtccgcag ccatctccag 600 gtgatgaccc ttgctattgg tgagtga 627 8 208 PRThomo sapiens 8 Met Ser Asp Thr Glu Tyr Ala Glu Trp Leu Arg Asn His PheLeu Ala 1 5 10 15 Glu Thr Ser Ile Asp Asn Arg Glu Glu Leu Leu Leu GluSer Ala Met 20 25 30 Arg Leu Glu Asn Lys Leu Thr Leu Leu Gly Ala Thr GlyIle Glu Asp 35 40 45 Arg Leu Gln Glu Gly Val Pro Glu Ser Ile Glu Ala LeuHis Lys Ala 50 55 60 Gly Ile Lys Ile Trp Met Leu Thr Gly Asp Lys Gln GluThr Ala Val 65 70 75 80 Asn Ile Ala Tyr Ala Cys Lys Leu Leu Glu Pro AspAsp Lys Leu Phe 85 90 95 Ile Leu Asn Thr Gln Ser Lys Asp Ala Cys Gly MetLeu Met Ser Thr 100 105 110 Ile Leu Lys Glu Leu Gln Lys Lys Thr Gln AlaLeu Pro Glu Gln Val 115 120 125 Ser Leu Ser Glu Asp Leu Leu Gln Pro ProVal Pro Arg Asp Ser Gly 130 135 140 Leu Arg Ala Gly Leu Ile Ile Thr GlyLys Thr Leu Glu Phe Ala Leu 145 150 155 160 Gln Glu Ser Leu Gln Lys GlnPhe Leu Glu Leu Thr Ser Trp Cys Gln 165 170 175 Ala Val Val Cys Cys ArgAla Thr Pro Leu Gln Lys Ser Glu Val Val 180 185 190 Lys Leu Val Arg SerHis Leu Gln Val Met Thr Leu Ala Ile Gly Glu 195 200 205 9 3813 DNA homosapiens 9 atgactgagg ctctccaatg ggccagatat cactggcgac ggctgatcagaggtgcaacc 60 agggatgatg attcagggcc atacaactat tcctcgttgc tcgcctgtgggcgcaagtcc 120 tctcagatcc ctaaactgtc aggaaggcac cggattgttg ttccccacatccagcccttc 180 aaggatgagt atgagaagtt ctccggagcc tatgtgaaca atcgaatacgaacaacaaag 240 tacacacttc tgaattttgt gccaagaaat ttatttgaac aatttcacagagctgccaat 300 ttatatttcc tgttcctagt tgtcctgaac tgggtacctt tggtagaagccttccaaaag 360 gaaatcacca tgttgcctct ggtggtggtc cttacaatta tcgcaattaaagatggcctg 420 gaagattatc ggaaatacaa aattgacaaa cagatcaata atttaataactaaagtttat 480 agtaggaaag agaaaaaata cattgaccga tgctggaaag acgttactgttggggacttt 540 attcgcctct cctgcaacga ggtcatccct gcagacatgg tactactcttttccactgat 600 ccagatggaa tctgtcacat tgagacttct ggtcttgatg gagagagcaatttaaaacag 660 aggcaggtgg ttcggggata tgcagaacag gactctgaag ttgatcctgagaagttttcc 720 agtaggatag aatgtgaaag cccaaacaat gacctcagca gattccgaggcttcctagaa 780 cattccaaca aagaacgcgt gggtctcagt aaagaaaatt tgttgcttagaggatgcacc 840 attagaaaca cagaggctgt tgtgggcatt gtggtttatg caggccatgaaaccaaagca 900 atgctgaaca acagtgggcc acggtataag cgcagcaaat tagaaagaagagcaaacaca 960 gatgtcctct ggtgtgtcat gcttctggtc ataatgtgct taactggcgcagtaggtcat 1020 ggaatctggc tgagcaggta tgaaaagatg cattttttca atgttcccgagcctgatgga 1080 catatcatat caccactgtt ggcaggattt tatatgtttt ggaccatgatcattttgtta 1140 caggtcttga ttcctatttc tctctatgtt tccatcgaaa ttgtgaagcttggacaaata 1200 tatttcattc aaagtgatgt ggatttctac aatgaaaaaa tggattctattgttcagtgc 1260 cgagccctga acatcgccga ggatctggga cagattcagt acctcttttccgataagaca 1320 ggaaccctca ctgagaataa gatggttttt cgaagatgta gtgtggcaggatttgattac 1380 tgccatgaag aaaatgccag gaggttggag tcctatcagg aagctgtctctgaagatgaa 1440 gattttatag acacagtcag tggttccctc agcaatatgg caaaaccgagagcccccagc 1500 tgcaggacag ttcataatgg gcctttggga aataagccct caaatcatcttgctgggagc 1560 tcttttactc taggaagtgg agaaggagcc agtgaagtgc ctcattccagacaggctgct 1620 ttcagtagcc ccattgaaac agacgtggta ccagacacca ggcttttagacaaatttagt 1680 cagattacac ctcggctctt tatgccacta gatgagacca tccaaaatccaccaatggaa 1740 actttgtaca ttatcgactt tttcattgca ttggcaattt gcaacacagtagtggtttct 1800 gctcctaacc aaccccgaca aaagatcaga cacccttcac tgggggggttgcccattaag 1860 tctttggaag agattaaaag tcttttccag agatggtctg tccgaagatcaagttctcca 1920 tcgcttaaca gtgggaaaga gccatcttct ggagttccaa acgcctttgtgagcagactc 1980 cctctcttta gtcgaatgaa accagcttca cctgtggagg aagaggtctcccaggtgtgt 2040 gagagccccc agtgctccag tagctcagct tgctgcacag aaacagagaaacaacacggt 2100 gatgcaggcc tcctgaatgg caaggcagag tccctccctg gacagccattggcctgcaac 2160 ctgtgttatg aggccgagag cccagacgaa gcggccttag tgtatgccgccagggcttac 2220 caatgcactt tacggtctcg gacaccagag caggtcatgg tggactttgctgctttggga 2280 ccattaacat ttcaactcct acacatcctg ccctttgact cagtaagaaaaagaatgtct 2340 gttgtggtcc gacaccctct ttccaatcaa gttgtggtgt atacgaaaggcgctgattct 2400 gtgatcatgg agttactgtc ggtggcttcc ccagatggag caagtctggagaaacaacag 2460 atgatagtaa gggagaaaac ccagaagcac ttggatgact atgccaaacaaggccttcgt 2520 actttatgta tagcaaagaa ggtcatgagt gacactgaat atgcagagtggctgaggaat 2580 cattttttag ctgaaaccag cattgacaac agggaagaat tactacttgaatctgccatg 2640 aggttggaga acaaacttac attacttggt gctactggca ttgaagaccgtctgcaggag 2700 ggagtccctg aatctataga agctcttcac aaagcgggca tcaagatctggatgctgaca 2760 ggggacaagc aggagacagc tgtcaacata gcttatgcat gcaaactactggagccagat 2820 gacaagcttt ttatcctcaa tacccaaagt aaagatgcct gtgggatgctgatgagcaca 2880 attttgaaag aacttcagaa gaaaactcaa gccctgccag agcaagtgtcattaagtgaa 2940 gatttacttc agcctcctgt cccccgggac tcagggttac gagctggactcattatcact 3000 gggaagaccc tggagtttgc cctgcaagaa agtctgcaaa agcagttcctggaactgaca 3060 tcttggtgtc aagctgtggt ctgctgccga gccacaccgc tgcagaaaagtgaagtggtg 3120 aaattggtcc gcagccatct ccaggtgatg acccttgcta ttggtgatggtgccaatgat 3180 gttagcatga tacaagtggc agacattggg ataggggtct caggtcaagaaggcatgcag 3240 gctgtgatgg ccagtgactt tgccgtttct cagttcaaac atctcagcaagctccttctt 3300 gtccatggac actggtgtta tacacggctt tccaacatga ttctctattttttctataag 3360 aatgtggcct atgtgaacct ccttttctgg taccagttct tttgtggattttcaggaaca 3420 tccatgactg attactgggt tttgatcttc ttcaacctcc tcttcacatctgcccctcct 3480 gtcatttatg gtgttttgga gaaagatgtg tctgcagaga ccctcatgcaactgcctgaa 3540 ctttacagaa gtggtcagaa atcagaggca tacttacccc ataccttctggatcacctta 3600 ttggatgctt tttatcaaag cctggtctgc ttctttgtgc cttattttacctaccagggc 3660 tcagatactg acatctttgc atttggaaac cccctgaaca cagccactctgttcatcgtt 3720 ctcctccatc tggtcattga aagcaagagt ttgaccaggt gcagtgactcacacctgcaa 3780 ttccagagct ttgggaggct gtggatcaca tga 3813 10 1270 PRThomo sapiens 10 Met Thr Glu Ala Leu Gln Trp Ala Arg Tyr His Trp Arg ArgLeu Ile 1 5 10 15 Arg Gly Ala Thr Arg Asp Asp Asp Ser Gly Pro Tyr AsnTyr Ser Ser 20 25 30 Leu Leu Ala Cys Gly Arg Lys Ser Ser Gln Ile Pro LysLeu Ser Gly 35 40 45 Arg His Arg Ile Val Val Pro His Ile Gln Pro Phe LysAsp Glu Tyr 50 55 60 Glu Lys Phe Ser Gly Ala Tyr Val Asn Asn Arg Ile ArgThr Thr Lys 65 70 75 80 Tyr Thr Leu Leu Asn Phe Val Pro Arg Asn Leu PheGlu Gln Phe His 85 90 95 Arg Ala Ala Asn Leu Tyr Phe Leu Phe Leu Val ValLeu Asn Trp Val 100 105 110 Pro Leu Val Glu Ala Phe Gln Lys Glu Ile ThrMet Leu Pro Leu Val 115 120 125 Val Val Leu Thr Ile Ile Ala Ile Lys AspGly Leu Glu Asp Tyr Arg 130 135 140 Lys Tyr Lys Ile Asp Lys Gln Ile AsnAsn Leu Ile Thr Lys Val Tyr 145 150 155 160 Ser Arg Lys Glu Lys Lys TyrIle Asp Arg Cys Trp Lys Asp Val Thr 165 170 175 Val Gly Asp Phe Ile ArgLeu Ser Cys Asn Glu Val Ile Pro Ala Asp 180 185 190 Met Val Leu Leu PheSer Thr Asp Pro Asp Gly Ile Cys His Ile Glu 195 200 205 Thr Ser Gly LeuAsp Gly Glu Ser Asn Leu Lys Gln Arg Gln Val Val 210 215 220 Arg Gly TyrAla Glu Gln Asp Ser Glu Val Asp Pro Glu Lys Phe Ser 225 230 235 240 SerArg Ile Glu Cys Glu Ser Pro Asn Asn Asp Leu Ser Arg Phe Arg 245 250 255Gly Phe Leu Glu His Ser Asn Lys Glu Arg Val Gly Leu Ser Lys Glu 260 265270 Asn Leu Leu Leu Arg Gly Cys Thr Ile Arg Asn Thr Glu Ala Val Val 275280 285 Gly Ile Val Val Tyr Ala Gly His Glu Thr Lys Ala Met Leu Asn Asn290 295 300 Ser Gly Pro Arg Tyr Lys Arg Ser Lys Leu Glu Arg Arg Ala AsnThr 305 310 315 320 Asp Val Leu Trp Cys Val Met Leu Leu Val Ile Met CysLeu Thr Gly 325 330 335 Ala Val Gly His Gly Ile Trp Leu Ser Arg Tyr GluLys Met His Phe 340 345 350 Phe Asn Val Pro Glu Pro Asp Gly His Ile IleSer Pro Leu Leu Ala 355 360 365 Gly Phe Tyr Met Phe Trp Thr Met Ile IleLeu Leu Gln Val Leu Ile 370 375 380 Pro Ile Ser Leu Tyr Val Ser Ile GluIle Val Lys Leu Gly Gln Ile 385 390 395 400 Tyr Phe Ile Gln Ser Asp ValAsp Phe Tyr Asn Glu Lys Met Asp Ser 405 410 415 Ile Val Gln Cys Arg AlaLeu Asn Ile Ala Glu Asp Leu Gly Gln Ile 420 425 430 Gln Tyr Leu Phe SerAsp Lys Thr Gly Thr Leu Thr Glu Asn Lys Met 435 440 445 Val Phe Arg ArgCys Ser Val Ala Gly Phe Asp Tyr Cys His Glu Glu 450 455 460 Asn Ala ArgArg Leu Glu Ser Tyr Gln Glu Ala Val Ser Glu Asp Glu 465 470 475 480 AspPhe Ile Asp Thr Val Ser Gly Ser Leu Ser Asn Met Ala Lys Pro 485 490 495Arg Ala Pro Ser Cys Arg Thr Val His Asn Gly Pro Leu Gly Asn Lys 500 505510 Pro Ser Asn His Leu Ala Gly Ser Ser Phe Thr Leu Gly Ser Gly Glu 515520 525 Gly Ala Ser Glu Val Pro His Ser Arg Gln Ala Ala Phe Ser Ser Pro530 535 540 Ile Glu Thr Asp Val Val Pro Asp Thr Arg Leu Leu Asp Lys PheSer 545 550 555 560 Gln Ile Thr Pro Arg Leu Phe Met Pro Leu Asp Glu ThrIle Gln Asn 565 570 575 Pro Pro Met Glu Thr Leu Tyr Ile Ile Asp Phe PheIle Ala Leu Ala 580 585 590 Ile Cys Asn Thr Val Val Val Ser Ala Pro AsnGln Pro Arg Gln Lys 595 600 605 Ile Arg His Pro Ser Leu Gly Gly Leu ProIle Lys Ser Leu Glu Glu 610 615 620 Ile Lys Ser Leu Phe Gln Arg Trp SerVal Arg Arg Ser Ser Ser Pro 625 630 635 640 Ser Leu Asn Ser Gly Lys GluPro Ser Ser Gly Val Pro Asn Ala Phe 645 650 655 Val Ser Arg Leu Pro LeuPhe Ser Arg Met Lys Pro Ala Ser Pro Val 660 665 670 Glu Glu Glu Val SerGln Val Cys Glu Ser Pro Gln Cys Ser Ser Ser 675 680 685 Ser Ala Cys CysThr Glu Thr Glu Lys Gln His Gly Asp Ala Gly Leu 690 695 700 Leu Asn GlyLys Ala Glu Ser Leu Pro Gly Gln Pro Leu Ala Cys Asn 705 710 715 720 LeuCys Tyr Glu Ala Glu Ser Pro Asp Glu Ala Ala Leu Val Tyr Ala 725 730 735Ala Arg Ala Tyr Gln Cys Thr Leu Arg Ser Arg Thr Pro Glu Gln Val 740 745750 Met Val Asp Phe Ala Ala Leu Gly Pro Leu Thr Phe Gln Leu Leu His 755760 765 Ile Leu Pro Phe Asp Ser Val Arg Lys Arg Met Ser Val Val Val Arg770 775 780 His Pro Leu Ser Asn Gln Val Val Val Tyr Thr Lys Gly Ala AspSer 785 790 795 800 Val Ile Met Glu Leu Leu Ser Val Ala Ser Pro Asp GlyAla Ser Leu 805 810 815 Glu Lys Gln Gln Met Ile Val Arg Glu Lys Thr GlnLys His Leu Asp 820 825 830 Asp Tyr Ala Lys Gln Gly Leu Arg Thr Leu CysIle Ala Lys Lys Val 835 840 845 Met Ser Asp Thr Glu Tyr Ala Glu Trp LeuArg Asn His Phe Leu Ala 850 855 860 Glu Thr Ser Ile Asp Asn Arg Glu GluLeu Leu Leu Glu Ser Ala Met 865 870 875 880 Arg Leu Glu Asn Lys Leu ThrLeu Leu Gly Ala Thr Gly Ile Glu Asp 885 890 895 Arg Leu Gln Glu Gly ValPro Glu Ser Ile Glu Ala Leu His Lys Ala 900 905 910 Gly Ile Lys Ile TrpMet Leu Thr Gly Asp Lys Gln Glu Thr Ala Val 915 920 925 Asn Ile Ala TyrAla Cys Lys Leu Leu Glu Pro Asp Asp Lys Leu Phe 930 935 940 Ile Leu AsnThr Gln Ser Lys Asp Ala Cys Gly Met Leu Met Ser Thr 945 950 955 960 IleLeu Lys Glu Leu Gln Lys Lys Thr Gln Ala Leu Pro Glu Gln Val 965 970 975Ser Leu Ser Glu Asp Leu Leu Gln Pro Pro Val Pro Arg Asp Ser Gly 980 985990 Leu Arg Ala Gly Leu Ile Ile Thr Gly Lys Thr Leu Glu Phe Ala Leu 9951000 1005 Gln Glu Ser Leu Gln Lys Gln Phe Leu Glu Leu Thr Ser Trp CysGln 1010 1015 1020 Ala Val Val Cys Cys Arg Ala Thr Pro Leu Gln Lys SerGlu Val Val 1025 1030 1035 1040 Lys Leu Val Arg Ser His Leu Gln Val MetThr Leu Ala Ile Gly Asp 1045 1050 1055 Gly Ala Asn Asp Val Ser Met IleGln Val Ala Asp Ile Gly Ile Gly 1060 1065 1070 Val Ser Gly Gln Glu GlyMet Gln Ala Val Met Ala Ser Asp Phe Ala 1075 1080 1085 Val Ser Gln PheLys His Leu Ser Lys Leu Leu Leu Val His Gly His 1090 1095 1100 Trp CysTyr Thr Arg Leu Ser Asn Met Ile Leu Tyr Phe Phe Tyr Lys 1105 1110 11151120 Asn Val Ala Tyr Val Asn Leu Leu Phe Trp Tyr Gln Phe Phe Cys Gly1125 1130 1135 Phe Ser Gly Thr Ser Met Thr Asp Tyr Trp Val Leu Ile PhePhe Asn 1140 1145 1150 Leu Leu Phe Thr Ser Ala Pro Pro Val Ile Tyr GlyVal Leu Glu Lys 1155 1160 1165 Asp Val Ser Ala Glu Thr Leu Met Gln LeuPro Glu Leu Tyr Arg Ser 1170 1175 1180 Gly Gln Lys Ser Glu Ala Tyr LeuPro His Thr Phe Trp Ile Thr Leu 1185 1190 1195 1200 Leu Asp Ala Phe TyrGln Ser Leu Val Cys Phe Phe Val Pro Tyr Phe 1205 1210 1215 Thr Tyr GlnGly Ser Asp Thr Asp Ile Phe Ala Phe Gly Asn Pro Leu 1220 1225 1230 AsnThr Ala Thr Leu Phe Ile Val Leu Leu His Leu Val Ile Glu Ser 1235 12401245 Lys Ser Leu Thr Arg Cys Ser Asp Ser His Leu Gln Phe Gln Ser Phe1250 1255 1260 Gly Arg Leu Trp Ile Thr 1265 1270 11 1269 DNA homosapiens 11 atgagtgaca ctgaatatgc agagtggctg aggaatcatt ttttagctgaaaccagcatt 60 gacaacaggg aagaattact acttgaatct gccatgaggt tggagaacaaacttacatta 120 cttggtgcta ctggcattga agaccgtctg caggagggag tccctgaatctatagaagct 180 cttcacaaag cgggcatcaa gatctggatg ctgacagggg acaagcaggagacagctgtc 240 aacatagctt atgcatgcaa actactggag ccagatgaca agctttttatcctcaatacc 300 caaagtaaag atgcctgtgg gatgctgatg agcacaattt tgaaagaacttcagaagaaa 360 actcaagccc tgccagagca agtgtcatta agtgaagatt tacttcagcctcctgtcccc 420 cgggactcag ggttacgagc tggactcatt atcactggga agaccctggagtttgccctg 480 caagaaagtc tgcaaaagca gttcctggaa ctgacatctt ggtgtcaagctgtggtctgc 540 tgccgagcca caccgctgca gaaaagtgaa gtggtgaaat tggtccgcagccatctccag 600 gtgatgaccc ttgctattgg tgatggtgcc aatgatgtta gcatgatacaagtggcagac 660 attgggatag gggtctcagg tcaagaaggc atgcaggctg tgatggccagtgactttgcc 720 gtttctcagt tcaaacatct cagcaagctc cttcttgtcc atggacactggtgttataca 780 cggctttcca acatgattct ctattttttc tataagaatg tggcctatgtgaacctcctt 840 ttctggtacc agttcttttg tggattttca ggaacatcca tgactgattactgggttttg 900 atcttcttca acctcctctt cacatctgcc cctcctgtca tttatggtgttttggagaaa 960 gatgtgtctg cagagaccct catgcaactg cctgaacttt acagaagtggtcagaaatca 1020 gaggcatact taccccatac cttctggatc accttattgg atgctttttatcaaagcctg 1080 gtctgcttct ttgtgcctta ttttacctac cagggctcag atactgacatctttgcattt 1140 ggaaaccccc tgaacacagc cactctgttc atcgttctcc tccatctggtcattgaaagc 1200 aagagtttga ccaggtgcag tgactcacac ctgcaattcc agagctttgggaggctgtgg 1260 atcacatga 1269 12 422 PRT homo sapiens 12 Met Ser AspThr Glu Tyr Ala Glu Trp Leu Arg Asn His Phe Leu Ala 1 5 10 15 Glu ThrSer Ile Asp Asn Arg Glu Glu Leu Leu Leu Glu Ser Ala Met 20 25 30 Arg LeuGlu Asn Lys Leu Thr Leu Leu Gly Ala Thr Gly Ile Glu Asp 35 40 45 Arg LeuGln Glu Gly Val Pro Glu Ser Ile Glu Ala Leu His Lys Ala 50 55 60 Gly IleLys Ile Trp Met Leu Thr Gly Asp Lys Gln Glu Thr Ala Val 65 70 75 80 AsnIle Ala Tyr Ala Cys Lys Leu Leu Glu Pro Asp Asp Lys Leu Phe 85 90 95 IleLeu Asn Thr Gln Ser Lys Asp Ala Cys Gly Met Leu Met Ser Thr 100 105 110Ile Leu Lys Glu Leu Gln Lys Lys Thr Gln Ala Leu Pro Glu Gln Val 115 120125 Ser Leu Ser Glu Asp Leu Leu Gln Pro Pro Val Pro Arg Asp Ser Gly 130135 140 Leu Arg Ala Gly Leu Ile Ile Thr Gly Lys Thr Leu Glu Phe Ala Leu145 150 155 160 Gln Glu Ser Leu Gln Lys Gln Phe Leu Glu Leu Thr Ser TrpCys Gln 165 170 175 Ala Val Val Cys Cys Arg Ala Thr Pro Leu Gln Lys SerGlu Val Val 180 185 190 Lys Leu Val Arg Ser His Leu Gln Val Met Thr LeuAla Ile Gly Asp 195 200 205 Gly Ala Asn Asp Val Ser Met Ile Gln Val AlaAsp Ile Gly Ile Gly 210 215 220 Val Ser Gly Gln Glu Gly Met Gln Ala ValMet Ala Ser Asp Phe Ala 225 230 235 240 Val Ser Gln Phe Lys His Leu SerLys Leu Leu Leu Val His Gly His 245 250 255 Trp Cys Tyr Thr Arg Leu SerAsn Met Ile Leu Tyr Phe Phe Tyr Lys 260 265 270 Asn Val Ala Tyr Val AsnLeu Leu Phe Trp Tyr Gln Phe Phe Cys Gly 275 280 285 Phe Ser Gly Thr SerMet Thr Asp Tyr Trp Val Leu Ile Phe Phe Asn 290 295 300 Leu Leu Phe ThrSer Ala Pro Pro Val Ile Tyr Gly Val Leu Glu Lys 305 310 315 320 Asp ValSer Ala Glu Thr Leu Met Gln Leu Pro Glu Leu Tyr Arg Ser 325 330 335 GlyGln Lys Ser Glu Ala Tyr Leu Pro His Thr Phe Trp Ile Thr Leu 340 345 350Leu Asp Ala Phe Tyr Gln Ser Leu Val Cys Phe Phe Val Pro Tyr Phe 355 360365 Thr Tyr Gln Gly Ser Asp Thr Asp Ile Phe Ala Phe Gly Asn Pro Leu 370375 380 Asn Thr Ala Thr Leu Phe Ile Val Leu Leu His Leu Val Ile Glu Ser385 390 395 400 Lys Ser Leu Thr Arg Cys Ser Asp Ser His Leu Gln Phe GlnSer Phe 405 410 415 Gly Arg Leu Trp Ile Thr 420 13 4281 DNA homo sapiens13 atgactgagg ctctccaatg ggccagatat cactggcgac ggctgatcag aggtgcaacc 60agggatgatg attcagggcc atacaactat tcctcgttgc tcgcctgtgg gcgcaagtcc 120tctcagatcc ctaaactgtc aggaaggcac cggattgttg ttccccacat ccagcccttc 180aaggatgagt atgagaagtt ctccggagcc tatgtgaaca atcgaatacg aacaacaaag 240tacacacttc tgaattttgt gccaagaaat ttatttgaac aatttcacag agctgccaat 300ttatatttcc tgttcctagt tgtcctgaac tgggtacctt tggtagaagc cttccaaaag 360gaaatcacca tgttgcctct ggtggtggtc cttacaatta tcgcaattaa agatggcctg 420gaagattatc ggaaatacaa aattgacaaa cagatcaata atttaataac taaagtttat 480agtaggaaag agaaaaaata cattgaccga tgctggaaag acgttactgt tggggacttt 540attcgcctct cctgcaacga ggtcatccct gcagacatgg tactactctt ttccactgat 600ccagatggaa tctgtcacat tgagacttct ggtcttgatg gagagagcaa tttaaaacag 660aggcaggtgg ttcggggata tgcagaacag gactctgaag ttgatcctga gaagttttcc 720agtaggatag aatgtgaaag cccaaacaat gacctcagca gattccgagg cttcctagaa 780cattccaaca aagaacgcgt gggtctcagt aaagaaaatt tgttgcttag aggatgcacc 840attagaaaca cagaggctgt tgtgggcatt gtggtttatg caggccatga aaccaaagca 900atgctgaaca acagtgggcc acggtataag cgcagcaaat tagaaagaag agcaaacaca 960gatgtcctct ggtgtgtcat gcttctggtc ataatgtgct taactggcgc agtaggtcat 1020ggaatctggc tgagcaggta tgaaaagatg cattttttca atgttcccga gcctgatgga 1080catatcatat caccactgtt ggcaggattt tatatgtttt ggaccatgat cattttgtta 1140caggtcttga ttcctatttc tctctatgtt tccatcgaaa ttgtgaagct tggacaaata 1200tatttcattc aaagtgatgt ggatttctac aatgaaaaaa tggattctat tgttcagtgc 1260cgagccctga acatcgccga ggatctggga cagattcagt acctcttttc cgataagaca 1320ggaaccctca ctgagaataa gatggttttt cgaagatgta gtgtggcagg atttgattac 1380tgccatgaag aaaatgccag gaggttggag tcctatcagg aagctgtctc tgaagatgaa 1440gattttatag acacagtcag tggttccctc agcaatatgg caaaaccgag agcccccagc 1500tgcaggacag ttcataatgg gcctttggga aataagccct caaatcatct tgctgggagc 1560tcttttactc taggaagtgg agaaggagcc agtgaagtgc ctcattccag acaggctgct 1620ttcagtagcc ccattgaaac agacgtggta ccagacacca ggcttttaga caaatttagt 1680cagattacac ctcggctctt tatgccacta gatgagacca tccaaaatcc accaatggaa 1740actttgtaca ttatcgactt tttcattgca ttggcaattt gcaacacagt agtggtttct 1800gctcctaacc aaccccgaca aaagatcaga cacccttcac tgggggggtt gcccattaag 1860tctttggaag agattaaaag tcttttccag agatggtctg tccgaagatc aagttctcca 1920tcgcttaaca gtgggaaaga gccatcttct ggagttccaa acgcctttgt gagcagactc 1980cctctcttta gtcgaatgaa accagcttca cctgtggagg aagaggtctc ccaggtgtgt 2040gagagccccc agtgctccag tagctcagct tgctgcacag aaacagagaa acaacacggt 2100gatgcaggcc tcctgaatgg caaggcagag tccctccctg gacagccatt ggcctgcaac 2160ctgtgttatg aggccgagag cccagacgaa gcggccttag tgtatgccgc cagggcttac 2220caatgcactt tacggtctcg gacaccagag caggtcatgg tggactttgc tgctttggga 2280ccattaacat ttcaactcct acacatcctg ccctttgact cagtaagaaa aagaatgtct 2340gttgtggtcc gacaccctct ttccaatcaa gttgtggtgt atacgaaagg cgctgattct 2400gtgatcatgg agttactgtc ggtggcttcc ccagatggag caagtctgga gaaacaacag 2460atgatagtaa gggagaaaac ccagaagcac ttggatgact atgccaaaca aggccttcgt 2520actttatgta tagcaaagaa ggtcatgagt gacactgaat atgcagagtg gctgaggaat 2580cattttttag ctgaaaccag cattgacaac agggaagaat tactacttga atctgccatg 2640aggttggaga acaaacttac attacttggt gctactggca ttgaagaccg tctgcaggag 2700ggagtccctg aatctataga agctcttcac aaagcgggca tcaagatctg gatgctgaca 2760ggggacaagc aggagacagc tgtcaacata gcttatgcat gcaaactact ggagccagat 2820gacaagcttt ttatcctcaa tacccaaagt aaagatgcct gtgggatgct gatgagcaca 2880attttgaaag aacttcagaa gaaaactcaa gccctgccag agcaagtgtc attaagtgaa 2940gatttacttc agcctcctgt cccccgggac tcagggttac gagctggact cattatcact 3000gggaagaccc tggagtttgc cctgcaagaa agtctgcaaa agcagttcct ggaactgaca 3060tcttggtgtc aagctgtggt ctgctgccga gccacaccgc tgcagaaaag tgaagtggtg 3120aaattggtcc gcagccatct ccaggtgatg acccttgcta ttggtgatgg tgccaatgat 3180gttagcatga tacaagtggc agacattggg ataggggtct caggtcaaga aggcatgcag 3240gctgtgatgg ccagtgactt tgccgtttct cagttcaaac atctcagcaa gctccttctt 3300gtccatggac actggtgtta tacacggctt tccaacatga ttctctattt tttctataag 3360aatgtggcct atgtgaacct ccttttctgg taccagttct tttgtggatt ttcaggaaca 3420tccatgactg attactgggt tttgatcttc ttcaacctcc tcttcacatc tgcccctcct 3480gtcatttatg gtgttttgga gaaagatgtg tctgcagaga ccctcatgca actgcctgaa 3540ctttacagaa gtggtcagaa atcagaggca tacttacccc ataccttctg gatcacctta 3600ttggatgctt tttatcaaag cctggtctgc ttctttgtgc cttattttac ctaccagggc 3660tcagatactg acatctttgc atttggaaac cccctgaaca cagccactct gttcatcgtt 3720ctcctccatc tggtcattga aagcaagagt ttgacttgga ttcacttgct ggtcatcatt 3780ggtagcatct tgtcttattt tttatttgcc atagtttttg gagccatgtg tgtaacttgc 3840aacccaccat ccaaccctta ctggattatg caggagcaca tgctggatcc agtattctac 3900ttagtttgta tcctcacgac gtccattgct cttctgccca ggtttgtata cagagttctt 3960cagggatccc tgtttccatc tccaattctg agagctaagc actttgacag actaactcca 4020gaggagagga ctaaagctct caagaagtgg agaggggctg gaaagatgaa tcaagtgaca 4080tcaaagtatg ctaaccaatc agctggcaag tcaggaagaa gacccatgcc tggcccttct 4140gctgtatttg caatgaagtc agcaacttcc tgtgctattg agcaaggaaa cttatctctg 4200tgtgaaactg ctttagatca aggctactct gaaactaagg cctttgagat ggctggaccc 4260tccaaaggta aagaaagcta g 4281 14 1426 PRT homo sapiens 14 Met Thr Glu AlaLeu Gln Trp Ala Arg Tyr His Trp Arg Arg Leu Ile 1 5 10 15 Arg Gly AlaThr Arg Asp Asp Asp Ser Gly Pro Tyr Asn Tyr Ser Ser 20 25 30 Leu Leu AlaCys Gly Arg Lys Ser Ser Gln Ile Pro Lys Leu Ser Gly 35 40 45 Arg His ArgIle Val Val Pro His Ile Gln Pro Phe Lys Asp Glu Tyr 50 55 60 Glu Lys PheSer Gly Ala Tyr Val Asn Asn Arg Ile Arg Thr Thr Lys 65 70 75 80 Tyr ThrLeu Leu Asn Phe Val Pro Arg Asn Leu Phe Glu Gln Phe His 85 90 95 Arg AlaAla Asn Leu Tyr Phe Leu Phe Leu Val Val Leu Asn Trp Val 100 105 110 ProLeu Val Glu Ala Phe Gln Lys Glu Ile Thr Met Leu Pro Leu Val 115 120 125Val Val Leu Thr Ile Ile Ala Ile Lys Asp Gly Leu Glu Asp Tyr Arg 130 135140 Lys Tyr Lys Ile Asp Lys Gln Ile Asn Asn Leu Ile Thr Lys Val Tyr 145150 155 160 Ser Arg Lys Glu Lys Lys Tyr Ile Asp Arg Cys Trp Lys Asp ValThr 165 170 175 Val Gly Asp Phe Ile Arg Leu Ser Cys Asn Glu Val Ile ProAla Asp 180 185 190 Met Val Leu Leu Phe Ser Thr Asp Pro Asp Gly Ile CysHis Ile Glu 195 200 205 Thr Ser Gly Leu Asp Gly Glu Ser Asn Leu Lys GlnArg Gln Val Val 210 215 220 Arg Gly Tyr Ala Glu Gln Asp Ser Glu Val AspPro Glu Lys Phe Ser 225 230 235 240 Ser Arg Ile Glu Cys Glu Ser Pro AsnAsn Asp Leu Ser Arg Phe Arg 245 250 255 Gly Phe Leu Glu His Ser Asn LysGlu Arg Val Gly Leu Ser Lys Glu 260 265 270 Asn Leu Leu Leu Arg Gly CysThr Ile Arg Asn Thr Glu Ala Val Val 275 280 285 Gly Ile Val Val Tyr AlaGly His Glu Thr Lys Ala Met Leu Asn Asn 290 295 300 Ser Gly Pro Arg TyrLys Arg Ser Lys Leu Glu Arg Arg Ala Asn Thr 305 310 315 320 Asp Val LeuTrp Cys Val Met Leu Leu Val Ile Met Cys Leu Thr Gly 325 330 335 Ala ValGly His Gly Ile Trp Leu Ser Arg Tyr Glu Lys Met His Phe 340 345 350 PheAsn Val Pro Glu Pro Asp Gly His Ile Ile Ser Pro Leu Leu Ala 355 360 365Gly Phe Tyr Met Phe Trp Thr Met Ile Ile Leu Leu Gln Val Leu Ile 370 375380 Pro Ile Ser Leu Tyr Val Ser Ile Glu Ile Val Lys Leu Gly Gln Ile 385390 395 400 Tyr Phe Ile Gln Ser Asp Val Asp Phe Tyr Asn Glu Lys Met AspSer 405 410 415 Ile Val Gln Cys Arg Ala Leu Asn Ile Ala Glu Asp Leu GlyGln Ile 420 425 430 Gln Tyr Leu Phe Ser Asp Lys Thr Gly Thr Leu Thr GluAsn Lys Met 435 440 445 Val Phe Arg Arg Cys Ser Val Ala Gly Phe Asp TyrCys His Glu Glu 450 455 460 Asn Ala Arg Arg Leu Glu Ser Tyr Gln Glu AlaVal Ser Glu Asp Glu 465 470 475 480 Asp Phe Ile Asp Thr Val Ser Gly SerLeu Ser Asn Met Ala Lys Pro 485 490 495 Arg Ala Pro Ser Cys Arg Thr ValHis Asn Gly Pro Leu Gly Asn Lys 500 505 510 Pro Ser Asn His Leu Ala GlySer Ser Phe Thr Leu Gly Ser Gly Glu 515 520 525 Gly Ala Ser Glu Val ProHis Ser Arg Gln Ala Ala Phe Ser Ser Pro 530 535 540 Ile Glu Thr Asp ValVal Pro Asp Thr Arg Leu Leu Asp Lys Phe Ser 545 550 555 560 Gln Ile ThrPro Arg Leu Phe Met Pro Leu Asp Glu Thr Ile Gln Asn 565 570 575 Pro ProMet Glu Thr Leu Tyr Ile Ile Asp Phe Phe Ile Ala Leu Ala 580 585 590 IleCys Asn Thr Val Val Val Ser Ala Pro Asn Gln Pro Arg Gln Lys 595 600 605Ile Arg His Pro Ser Leu Gly Gly Leu Pro Ile Lys Ser Leu Glu Glu 610 615620 Ile Lys Ser Leu Phe Gln Arg Trp Ser Val Arg Arg Ser Ser Ser Pro 625630 635 640 Ser Leu Asn Ser Gly Lys Glu Pro Ser Ser Gly Val Pro Asn AlaPhe 645 650 655 Val Ser Arg Leu Pro Leu Phe Ser Arg Met Lys Pro Ala SerPro Val 660 665 670 Glu Glu Glu Val Ser Gln Val Cys Glu Ser Pro Gln CysSer Ser Ser 675 680 685 Ser Ala Cys Cys Thr Glu Thr Glu Lys Gln His GlyAsp Ala Gly Leu 690 695 700 Leu Asn Gly Lys Ala Glu Ser Leu Pro Gly GlnPro Leu Ala Cys Asn 705 710 715 720 Leu Cys Tyr Glu Ala Glu Ser Pro AspGlu Ala Ala Leu Val Tyr Ala 725 730 735 Ala Arg Ala Tyr Gln Cys Thr LeuArg Ser Arg Thr Pro Glu Gln Val 740 745 750 Met Val Asp Phe Ala Ala LeuGly Pro Leu Thr Phe Gln Leu Leu His 755 760 765 Ile Leu Pro Phe Asp SerVal Arg Lys Arg Met Ser Val Val Val Arg 770 775 780 His Pro Leu Ser AsnGln Val Val Val Tyr Thr Lys Gly Ala Asp Ser 785 790 795 800 Val Ile MetGlu Leu Leu Ser Val Ala Ser Pro Asp Gly Ala Ser Leu 805 810 815 Glu LysGln Gln Met Ile Val Arg Glu Lys Thr Gln Lys His Leu Asp 820 825 830 AspTyr Ala Lys Gln Gly Leu Arg Thr Leu Cys Ile Ala Lys Lys Val 835 840 845Met Ser Asp Thr Glu Tyr Ala Glu Trp Leu Arg Asn His Phe Leu Ala 850 855860 Glu Thr Ser Ile Asp Asn Arg Glu Glu Leu Leu Leu Glu Ser Ala Met 865870 875 880 Arg Leu Glu Asn Lys Leu Thr Leu Leu Gly Ala Thr Gly Ile GluAsp 885 890 895 Arg Leu Gln Glu Gly Val Pro Glu Ser Ile Glu Ala Leu HisLys Ala 900 905 910 Gly Ile Lys Ile Trp Met Leu Thr Gly Asp Lys Gln GluThr Ala Val 915 920 925 Asn Ile Ala Tyr Ala Cys Lys Leu Leu Glu Pro AspAsp Lys Leu Phe 930 935 940 Ile Leu Asn Thr Gln Ser Lys Asp Ala Cys GlyMet Leu Met Ser Thr 945 950 955 960 Ile Leu Lys Glu Leu Gln Lys Lys ThrGln Ala Leu Pro Glu Gln Val 965 970 975 Ser Leu Ser Glu Asp Leu Leu GlnPro Pro Val Pro Arg Asp Ser Gly 980 985 990 Leu Arg Ala Gly Leu Ile IleThr Gly Lys Thr Leu Glu Phe Ala Leu 995 1000 1005 Gln Glu Ser Leu GlnLys Gln Phe Leu Glu Leu Thr Ser Trp Cys Gln 1010 1015 1020 Ala Val ValCys Cys Arg Ala Thr Pro Leu Gln Lys Ser Glu Val Val 1025 1030 1035 1040Lys Leu Val Arg Ser His Leu Gln Val Met Thr Leu Ala Ile Gly Asp 10451050 1055 Gly Ala Asn Asp Val Ser Met Ile Gln Val Ala Asp Ile Gly IleGly 1060 1065 1070 Val Ser Gly Gln Glu Gly Met Gln Ala Val Met Ala SerAsp Phe Ala 1075 1080 1085 Val Ser Gln Phe Lys His Leu Ser Lys Leu LeuLeu Val His Gly His 1090 1095 1100 Trp Cys Tyr Thr Arg Leu Ser Asn MetIle Leu Tyr Phe Phe Tyr Lys 1105 1110 1115 1120 Asn Val Ala Tyr Val AsnLeu Leu Phe Trp Tyr Gln Phe Phe Cys Gly 1125 1130 1135 Phe Ser Gly ThrSer Met Thr Asp Tyr Trp Val Leu Ile Phe Phe Asn 1140 1145 1150 Leu LeuPhe Thr Ser Ala Pro Pro Val Ile Tyr Gly Val Leu Glu Lys 1155 1160 1165Asp Val Ser Ala Glu Thr Leu Met Gln Leu Pro Glu Leu Tyr Arg Ser 11701175 1180 Gly Gln Lys Ser Glu Ala Tyr Leu Pro His Thr Phe Trp Ile ThrLeu 1185 1190 1195 1200 Leu Asp Ala Phe Tyr Gln Ser Leu Val Cys Phe PheVal Pro Tyr Phe 1205 1210 1215 Thr Tyr Gln Gly Ser Asp Thr Asp Ile PheAla Phe Gly Asn Pro Leu 1220 1225 1230 Asn Thr Ala Thr Leu Phe Ile ValLeu Leu His Leu Val Ile Glu Ser 1235 1240 1245 Lys Ser Leu Thr Trp IleHis Leu Leu Val Ile Ile Gly Ser Ile Leu 1250 1255 1260 Ser Tyr Phe LeuPhe Ala Ile Val Phe Gly Ala Met Cys Val Thr Cys 1265 1270 1275 1280 AsnPro Pro Ser Asn Pro Tyr Trp Ile Met Gln Glu His Met Leu Asp 1285 12901295 Pro Val Phe Tyr Leu Val Cys Ile Leu Thr Thr Ser Ile Ala Leu Leu1300 1305 1310 Pro Arg Phe Val Tyr Arg Val Leu Gln Gly Ser Leu Phe ProSer Pro 1315 1320 1325 Ile Leu Arg Ala Lys His Phe Asp Arg Leu Thr ProGlu Glu Arg Thr 1330 1335 1340 Lys Ala Leu Lys Lys Trp Arg Gly Ala GlyLys Met Asn Gln Val Thr 1345 1350 1355 1360 Ser Lys Tyr Ala Asn Gln SerAla Gly Lys Ser Gly Arg Arg Pro Met 1365 1370 1375 Pro Gly Pro Ser AlaVal Phe Ala Met Lys Ser Ala Thr Ser Cys Ala 1380 1385 1390 Ile Glu GlnGly Asn Leu Ser Leu Cys Glu Thr Ala Leu Asp Gln Gly 1395 1400 1405 TyrSer Glu Thr Lys Ala Phe Glu Met Ala Gly Pro Ser Lys Gly Lys 1410 14151420 Glu Ser 1425 15 1737 DNA homo sapiens 15 atgagtgaca ctgaatatgcagagtggctg aggaatcatt ttttagctga aaccagcatt 60 gacaacaggg aagaattactacttgaatct gccatgaggt tggagaacaa acttacatta 120 cttggtgcta ctggcattgaagaccgtctg caggagggag tccctgaatc tatagaagct 180 cttcacaaag cgggcatcaagatctggatg ctgacagggg acaagcagga gacagctgtc 240 aacatagctt atgcatgcaaactactggag ccagatgaca agctttttat cctcaatacc 300 caaagtaaag atgcctgtgggatgctgatg agcacaattt tgaaagaact tcagaagaaa 360 actcaagccc tgccagagcaagtgtcatta agtgaagatt tacttcagcc tcctgtcccc 420 cgggactcag ggttacgagctggactcatt atcactggga agaccctgga gtttgccctg 480 caagaaagtc tgcaaaagcagttcctggaa ctgacatctt ggtgtcaagc tgtggtctgc 540 tgccgagcca caccgctgcagaaaagtgaa gtggtgaaat tggtccgcag ccatctccag 600 gtgatgaccc ttgctattggtgatggtgcc aatgatgtta gcatgataca agtggcagac 660 attgggatag gggtctcaggtcaagaaggc atgcaggctg tgatggccag tgactttgcc 720 gtttctcagt tcaaacatctcagcaagctc cttcttgtcc atggacactg gtgttataca 780 cggctttcca acatgattctctattttttc tataagaatg tggcctatgt gaacctcctt 840 ttctggtacc agttcttttgtggattttca ggaacatcca tgactgatta ctgggttttg 900 atcttcttca acctcctcttcacatctgcc cctcctgtca tttatggtgt tttggagaaa 960 gatgtgtctg cagagaccctcatgcaactg cctgaacttt acagaagtgg tcagaaatca 1020 gaggcatact taccccataccttctggatc accttattgg atgcttttta tcaaagcctg 1080 gtctgcttct ttgtgccttattttacctac cagggctcag atactgacat ctttgcattt 1140 ggaaaccccc tgaacacagccactctgttc atcgttctcc tccatctggt cattgaaagc 1200 aagagtttga cttggattcacttgctggtc atcattggta gcatcttgtc ttatttttta 1260 tttgccatag tttttggagccatgtgtgta acttgcaacc caccatccaa cccttactgg 1320 attatgcagg agcacatgctggatccagta ttctacttag tttgtatcct cacgacgtcc 1380 attgctcttc tgcccaggtttgtatacaga gttcttcagg gatccctgtt tccatctcca 1440 attctgagag ctaagcactttgacagacta actccagagg agaggactaa agctctcaag 1500 aagtggagag gggctggaaagatgaatcaa gtgacatcaa agtatgctaa ccaatcagct 1560 ggcaagtcag gaagaagacccatgcctggc ccttctgctg tatttgcaat gaagtcagca 1620 acttcctgtg ctattgagcaaggaaactta tctctgtgtg aaactgcttt agatcaaggc 1680 tactctgaaa ctaaggcctttgagatggct ggaccctcca aaggtaaaga aagctag 1737 16 578 PRT homo sapiens 16Met Ser Asp Thr Glu Tyr Ala Glu Trp Leu Arg Asn His Phe Leu Ala 1 5 1015 Glu Thr Ser Ile Asp Asn Arg Glu Glu Leu Leu Leu Glu Ser Ala Met 20 2530 Arg Leu Glu Asn Lys Leu Thr Leu Leu Gly Ala Thr Gly Ile Glu Asp 35 4045 Arg Leu Gln Glu Gly Val Pro Glu Ser Ile Glu Ala Leu His Lys Ala 50 5560 Gly Ile Lys Ile Trp Met Leu Thr Gly Asp Lys Gln Glu Thr Ala Val 65 7075 80 Asn Ile Ala Tyr Ala Cys Lys Leu Leu Glu Pro Asp Asp Lys Leu Phe 8590 95 Ile Leu Asn Thr Gln Ser Lys Asp Ala Cys Gly Met Leu Met Ser Thr100 105 110 Ile Leu Lys Glu Leu Gln Lys Lys Thr Gln Ala Leu Pro Glu GlnVal 115 120 125 Ser Leu Ser Glu Asp Leu Leu Gln Pro Pro Val Pro Arg AspSer Gly 130 135 140 Leu Arg Ala Gly Leu Ile Ile Thr Gly Lys Thr Leu GluPhe Ala Leu 145 150 155 160 Gln Glu Ser Leu Gln Lys Gln Phe Leu Glu LeuThr Ser Trp Cys Gln 165 170 175 Ala Val Val Cys Cys Arg Ala Thr Pro LeuGln Lys Ser Glu Val Val 180 185 190 Lys Leu Val Arg Ser His Leu Gln ValMet Thr Leu Ala Ile Gly Asp 195 200 205 Gly Ala Asn Asp Val Ser Met IleGln Val Ala Asp Ile Gly Ile Gly 210 215 220 Val Ser Gly Gln Glu Gly MetGln Ala Val Met Ala Ser Asp Phe Ala 225 230 235 240 Val Ser Gln Phe LysHis Leu Ser Lys Leu Leu Leu Val His Gly His 245 250 255 Trp Cys Tyr ThrArg Leu Ser Asn Met Ile Leu Tyr Phe Phe Tyr Lys 260 265 270 Asn Val AlaTyr Val Asn Leu Leu Phe Trp Tyr Gln Phe Phe Cys Gly 275 280 285 Phe SerGly Thr Ser Met Thr Asp Tyr Trp Val Leu Ile Phe Phe Asn 290 295 300 LeuLeu Phe Thr Ser Ala Pro Pro Val Ile Tyr Gly Val Leu Glu Lys 305 310 315320 Asp Val Ser Ala Glu Thr Leu Met Gln Leu Pro Glu Leu Tyr Arg Ser 325330 335 Gly Gln Lys Ser Glu Ala Tyr Leu Pro His Thr Phe Trp Ile Thr Leu340 345 350 Leu Asp Ala Phe Tyr Gln Ser Leu Val Cys Phe Phe Val Pro TyrPhe 355 360 365 Thr Tyr Gln Gly Ser Asp Thr Asp Ile Phe Ala Phe Gly AsnPro Leu 370 375 380 Asn Thr Ala Thr Leu Phe Ile Val Leu Leu His Leu ValIle Glu Ser 385 390 395 400 Lys Ser Leu Thr Trp Ile His Leu Leu Val IleIle Gly Ser Ile Leu 405 410 415 Ser Tyr Phe Leu Phe Ala Ile Val Phe GlyAla Met Cys Val Thr Cys 420 425 430 Asn Pro Pro Ser Asn Pro Tyr Trp IleMet Gln Glu His Met Leu Asp 435 440 445 Pro Val Phe Tyr Leu Val Cys IleLeu Thr Thr Ser Ile Ala Leu Leu 450 455 460 Pro Arg Phe Val Tyr Arg ValLeu Gln Gly Ser Leu Phe Pro Ser Pro 465 470 475 480 Ile Leu Arg Ala LysHis Phe Asp Arg Leu Thr Pro Glu Glu Arg Thr 485 490 495 Lys Ala Leu LysLys Trp Arg Gly Ala Gly Lys Met Asn Gln Val Thr 500 505 510 Ser Lys TyrAla Asn Gln Ser Ala Gly Lys Ser Gly Arg Arg Pro Met 515 520 525 Pro GlyPro Ser Ala Val Phe Ala Met Lys Ser Ala Thr Ser Cys Ala 530 535 540 IleGlu Gln Gly Asn Leu Ser Leu Cys Glu Thr Ala Leu Asp Gln Gly 545 550 555560 Tyr Ser Glu Thr Lys Ala Phe Glu Met Ala Gly Pro Ser Lys Gly Lys 565570 575 Glu Ser 17 5958 DNA homo sapiens 17 gtcagctaca caacctggatcttaccacag tttggatatg actgaggctc tccaatgggc 60 cagatatcac tggcgacggctgatcagagg tgcaaccagg gatgatgatt cagggccata 120 caactattcc tcgttgctcgcctgtgggcg caagtcctct cagatcccta aactgtcagg 180 aaggcaccgg attgttgttccccacatcca gcccttcaag gatgagtatg agaagttctc 240 cggagcctat gtgaacaatcgaatacgaac aacaaagtac acacttctga attttgtgcc 300 aagaaattta tttgaacaatttcacagagc tgccaattta tatttcctgt tcctagttgt 360 cctgaactgg gtacctttggtagaagcctt ccaaaaggaa atcaccatgt tgcctctggt 420 ggtggtcctt acaattatcgcaattaaaga tggcctggaa gattatcgga aatacaaaat 480 tgacaaacag atcaataatttaataactaa agtttatagt aggaaagaga aaaaatacat 540 tgaccgatgc tggaaagacgttactgttgg ggactttatt cgcctctcct gcaacgaggt 600 catccctgca gacatggtactactcttttc cactgatcca gatggaatct gtcacattga 660 gacttctggt cttgatggagagagcaattt aaaacagagg caggtggttc ggggatatgc 720 agaacaggac tctgaagttgatcctgagaa gttttccagt aggatagaat gtgaaagccc 780 aaacaatgac ctcagcagattccgaggctt cctagaacat tccaacaaag aacgcgtggg 840 tctcagtaaa gaaaatttgttgcttagagg atgcaccatt agaaacacag aggctgttgt 900 gggcattgtg gtttatgcaggccatgaaac caaagcaatg ctgaacaaca gtgggccacg 960 gtataagcgc agcaaattagaaagaagagc aaacacagat gtcctctggt gtgtcatgct 1020 tctggtcata atgtgcttaactggcgcagt aggtcatgga atctggctga gcaggtatga 1080 aaagatgcat tttttcaatgttcccgagcc tgatggacat atcatatcac cactgttggc 1140 aggattttat atgttttggaccatgatcat tttgttacag gtcttgattc ctatttctct 1200 ctatgtttcc atcgaaattgtgaagcttgg acaaatatat ttcattcaaa gtgatgtgga 1260 tttctacaat gaaaaaatggattctattgt tcagtgccga gccctgaaca tcgccgagga 1320 tctgggacag attcagtacctcttttccga taagacagga accctcactg agaataagat 1380 ggtttttcga agatgtagtgtggcaggatt tgattactgc catgaagaaa atgccaggag 1440 gttggagtcc tatcaggaagctgtctctga agatgaagat tttatagaca cagtcagtgg 1500 ttccctcagc aatatggcaaaaccgagagc ccccagctgc aggacagttc ataatgggcc 1560 tttgggaaat aagccctcaaatcatcttgc tgggagctct tttactctag gaagtggaga 1620 aggagccagt gaagtgcctcattccagaca ggctgctttc agtagcccca ttgaaacaga 1680 cgtggtacca gacaccaggcttttagacaa atttagtcag attacacctc ggctctttat 1740 gccactagat gagaccatccaaaatccacc aatggaaact ttgtacatta tcgacttttt 1800 cattgcattg gcaatttgcaacacagtagt ggtttctgct cctaaccaac cccgacaaaa 1860 gatcagacac ccttcactgggggggttgcc cattaagtct ttggaagaga ttaaaagtct 1920 tttccagaga tggtctgtccgaagatcaag ttctccatcg cttaacagtg ggaaagagcc 1980 atcttctgga gttccaaacgcctttgtgag cagactccct ctctttagtc gaatgaaacc 2040 agcttcacct gtggaggaagaggtctccca ggtgtgtgag agcccccagt gctccagtag 2100 ctcagcttgc tgcacagaaacagagaaaca acacggtgat gcaggcctcc tgaatggcaa 2160 ggcagagtcc ctccctggacagccattggc ctgcaacctg tgttatgagg ccgagagccc 2220 agacgaagcg gccttagtgtatgccgccag ggcttaccaa tgcactttac ggtctcggac 2280 accagagcag gtcatggtggactttgctgc tttgggacca ttaacatttc aactcctaca 2340 catcctgccc tttgactcagtaagaaaaag aatgtctgtt gtggtccgac accctctttc 2400 caatcaagtt gtggtgtatacgaaaggcgc tgattctgtg atcatggagt tactgtcggt 2460 ggcttcccca gatggagcaagtctggagaa acaacagatg atagtaaggg agaaaaccca 2520 gaagcacttt tttcttccatttcaggtgtc gtgaaaagct tgaattcggc gcgccagata 2580 tcacgcgtgc caagggactggctcaggatg actatgccaa acaaggcctt cgtactttat 2640 gtatagcaaa gaaggtcatgagtgacactg aatatgcaga gtggctgagg aatcattttt 2700 tagctgaaac cagcattgacaacagggaag aattactact tgaatctgcc atgaggttgg 2760 agaacaaact tacattacttggtgctactg gcattgaaga ccgtctgcag gagggagtcc 2820 ctgaatctat agaagctcttcacaaagcgg gcatcaagat ctggatgctg acaggggaca 2880 agcaggagac agctgtcaacatagcttatg catgcaaact actggagcca gatgacaagc 2940 tttttatcct caatacccaaagtaaagtgc gtatattgag attaaatctg ttcttctgta 3000 ttttcaaagg cattggaacatttgagattt gatgtatgca aggattaaaa aaatgcctgt 3060 gggatgctga tgagcacaattttgaaagaa cttcagaaga aaactcaagc cctgccagag 3120 caagtgtcat taagtgaagatttacttcag cctcctgtcc cccgggactc agggttacga 3180 gctggactca ttatcactgggaagaccctg gagtttgccc tgcaagaaag tctgcaaaag 3240 cagttcctgg aactgacatcttggtgtcaa gctgtggtct gctgccgagc cacaccgctg 3300 cagaaaagtg aagtggtgaaattggtccgc agccatctcc aggtgatgac ccttgctatt 3360 ggtgagtgag gatgaatctgagtcctgctc ttctcccttt cacaccacac cagacaccga 3420 tccttctgtc tctttcttctcccactgttc cttccatttt cctcctccct ttttctctac 3480 cacattcatg ccttcccatcacctatttga gcaccttcct ccatcaccta tttgagcacc 3540 ttctgtgaac caggtaatagggatgtgaca tggtaaacaa tacagtagtc cagacttctt 3600 agttcagtgt cagacccccaaatcaacaag cttaaatcaa gtaataaact gaatcacaga 3660 actgaaaaat ccatgtgttctaccttcagg aaagctaaat tcaaggacat gagaattcat 3720 ttctttatcc attccacaagtatttatcaa gtgccttttt tgtaccaggc atttttctag 3780 atggagatac aagagtatataaaattggca aactaccttt ttacaaggaa cttacatcta 3840 gtaggaaggc atgcagttaaacaaagcata atctgtcagg ttcaggtagt gataagtact 3900 attggaaaaa taagtggatgaggacacgta tagcactgga gatgggctgg ggctgctctt 3960 taaatcgatt tcaagagctactgtaagttg actgggagca gagatgtgaa ggaaatcata 4020 aggggccatg gagacatggtggtgccaatg atgttagcat gatacaagtg gcagacattg 4080 ggataggggt ctcaggtcaagaaggcatgc aggctgtgat ggccagtgac tttgccgttt 4140 ctcagttcaa acatctcagcaagctccttc ttgtccatgg acactggtgt tatacacggc 4200 tttccaacat gattctctattttttctata agaatgtggc ctatgtgaac ctccttttct 4260 ggtaccagtt cttttgtggattttcaggaa catccatgac tgattactgg gttttgatct 4320 tcttcaacct cctcttcacatctgcccctc ctgtcattta tggtgttttg gagaaagatg 4380 tgtctgcaga gaccctcatgcaactgcctg aactttacag aagtggtcag aaatcagagg 4440 catacttacc ccataccttctggatcacct tattggatgc tttttatcaa agcctggtct 4500 gcttctttgt gccttattttacctaccagg gctcagatac tgacatcttt gcatttggaa 4560 accccctgaa cacagccactctgttcatcg ttctcctcca tctggtcatt gaaagcaaga 4620 gtttgaccag gtgcagtgactcacacctgc aattccagag ctttgggagg ctgtggatca 4680 catgaagcta agagttcaagaccagcctgg gcaacataac ttggattcac ttgctggtca 4740 tcattggtag catcttgtcttattttttat ttgccatagt ttttggagcc atgtgtgtaa 4800 cttgcaaccc accatccaacccttactgga ttatgcagga gcacatgctg gatccagtat 4860 tctacttagt ttgtatcctcacgacgtcca ttgctcttct gcccaggttt gtatacagag 4920 ttcttcaggg atccctgtttccatctccaa ttctgagagc taagcacttt gacagactaa 4980 ctccagagga gaggactaaagctctcaaga agtggagagg ggctggaaag atgaatcaag 5040 tgacatcaaa gtatgctaaccaatcagctg gcaagtcagg aagaagaccc atgcctggcc 5100 cttctgctgt atttgcaatgaagtcagcaa cttcctgtgc tattgagcaa ggaaacttat 5160 ctctgtgtga aactgctttagatcaaggct actctgaaac taaggccttt gagatggctg 5220 gaccctccaa aggtaaagaaagctagatac cctccttgga gttgcaagta ttctttcaag 5280 gttggaagag ggattttgaagaggtatctc tccaagcaag aatgacttgt ttttccataa 5340 gggacatgag cattttactaggcttggaag agctgacatg atgagcatta ttgtatgttt 5400 gtatatacat ttgtgatagagggctagagt ttgacctaga gagagtttaa ggaagtgaaa 5460 tatttaattc agaaccaaatgcttttgtaa aactttttgg attttgtaaa agcattttca 5520 ttctcttaga aattcaagtattttcaaggg gagtcatttg agatatattt attttactag 5580 gagatcttat attctagggaaatgctttaa atggtcaggc tccaatcgga atttttttaa 5640 gaaaaaagta gtttttaatacattggttag gactcagagg aaatacggaa aaaacattgt 5700 agatggtaat ttacagataaaatcccaaga gcctttaaac aacaaggtac ctaaataggg 5760 tataattata ctgcttaaaatacaggtagt gcctattaat agctttttat ttcctatggg 5820 gagatgcttt ggtcttctggctgagatgta ggcatacctc tcactcattt caatgctttc 5880 ctgaggtgga gccttcattggaaaggggaa agagggttct aggttcatca gggaccagga 5940 atgctttcct ctggcagg5958

What is claimed is:
 1. An isolated nucleic acid molecule comprising thenovel human ATPase nucleotide sequence described in SEQ ID NO:
 13. 2. Anisolated nucleic acid molecule comprising a novel human ATPasenucleotide sequence that: (a) encodes the amino acid sequence shown inSEQ ID NO:14; and (b) hybridizes under highly stringent conditions tothe nucleotide sequence of SEQ ID NO:13, wherein the highly stringentconditions are: hybridization in 0.5 M NaHPO₄, 7% sodium dodecyl sulfate(SDS), and 1 mM EDTA at 65° C. and washing in 0.1×SSC/0.1% SDS at 68° C.3. An isolated nucleic acid molecule comprising a human ATPasenucleotide sequence encoding the amino acid sequence of SEQ ID NO: 14.